Fused Pyrazoles as FGFR Inhibitors

ABSTRACT

The present invention relates to fused pyrazole derivatives, and pharmaceutical compositions including the same, that are inhibitors of one or more FGFR enzymes and are useful in the treatment of FGFR-associated diseases such as cancer.

FIELD OF THE INVENTION

The present invention relates to fused pyrazole derivatives, andpharmaceutical compositions including the same, that are inhibitors ofone or more FGFR enzymes and are useful in the treatment ofFGFR-associated diseases such as cancer.

BACKGROUND OF THE INVENTION

The Fibroblast Growth Factor Receptors (FGFR) are receptor tyrosinekinases that bind to fibroblast growth factor (FGF) ligands. There arefour FGFR proteins (FGFR1-4) that are capable of binding ligands and areinvolved in the regulation of many physiological processes includingtissue development, angiogenesis, wound healing, and metabolicregulation. Upon ligand binding, the receptors undergo dimerization andphosphorylation leading to stimulation of the protein kinase activityand recruitment of many intracellular docking proteins. Theseinteractions facilitate the activation of an array of intracellularsignaling pathways including Ras-MAPK, AKT-PI3K, and phospholipase Cthat are important for cellular growth, proliferation and survival(Reviewed in Eswarakumar et al. Cytokine & Growth Factor Reviews, 16,139-149 (2005)). Aberrant activation of this pathway either throughoverexpression of FGF ligands or FGFR or activating mutations in theFGFRs can lead to tumor development, progression, and resistance toconventional cancer therapies. In human cancer, genetic alterationsincluding gene amplification, chromosomal translocations and somaticmutations that lead to ligand-independent receptor activation have beendescribed. Large scale DNA sequencing of thousands of tumor samples hasrevealed that components of the FGFR pathway are among the mostfrequently mutated in human cancer. Many of these activating mutationsare identical to germline mutations that lead to skeletal dysplasiasyndromes. Mechanisms that lead to aberrant ligand-dependent signalingin human disease include overexpression of FGFs and changes in FGFRsplicing that lead to receptors with more promiscuous ligand bindingabilities (Reviewed in Knights and Cook, Pharmacology & Therapeutics,125, 105-117 (2010); Turner and Grose, Nature Reviews Cancer, 10,116-129 (2010)). Therefore, development of inhibitors targeting FGFR maybe useful in the clinical treatment of diseases that have elevated FGFor FGFR activity.

The cancer types in which FGF/FGFRs are implicated include, but are notlimited to: carcinomas (e.g., bladder, breast, cervical, colorectal,endometrial, gastric, head and neck, kidney, liver, lung, ovarian,prostate); hematopoietic malignancies (e.g., multiple myeloma, chroniclymphocytic lymphoma, adult T cell leukemia, acute myelogenous leukemia,non-Hodgkin lymphoma, myeloproliferative neoplasms, and Waldenstrom'sMacroglubulinemia); and other neoplasms (e.g., glioblastoma, melanoma,and rhabdosarcoma). In addition to a role in oncogenic neoplasms, FGFRactivation has also been implicated in skeletal and chondrocytedisorders including, but not limited to, achrondroplasia andcraniosynostosis syndromes.

There is a continuing need for the development of new drugs for thetreatment of cancer and other diseases, and the FGFR inhibitorsdescribed herein help address this need.

SUMMARY OF THE INVENTION

The present invention provides, inter alia, a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein constituentvariables are defined herein.

The present invention further provides a pharmaceutical compositioncomprising a compound of Formula I and at least one pharmaceuticallyacceptable carrier.

The present invention further provides a method of treating cancer in apatient comprising administering to the patient a therapeuticallyeffective amount of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof.

The present invention further provides a method of treating amyeloproliferative disorder in a patient comprising administering to thepatient a therapeutically effective amount of a compound of Formula I,or a pharmaceutically acceptable salt thereof.

The present invention further provides a skeletal or chondrocytedisorder in a patient comprising administering to the patient atherapeutically effective amount of Formula I, or a pharmaceuticallyacceptable salt thereof.

The present invention further provides a compound of Formula I for usein therapy.

The present invention further provides use of a compound of Formula I intherapy.

The present invention further provides the use of a compound of FormulaI for the preparation of a medicament for use in therapy.

DETAILED DESCRIPTION

The present invention provides an FGFR inhibitor of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

W is N or CR⁶;

Y is N or CR⁷;

Z is N or CR⁸;

wherein one or two of W, Y, and Z is N;

L is absent or selected from C₂₋₆ alkenylene, C₃₋₆ heteroalkenylene,C₂₋₆ alkynylene, and C₃₋₆ heteroalkynylene, wherein said C₂₋₆alkenylene, C₃₋₆ heteroalkenylene, C₂₋₆ alkynylene, and C₃₋₆heteroalkynylene are each optionally substituted with 1, 2, or 3substituents independently selected from halo, CN, NO₂, OR^(a), C₁₋₄alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, C(O)NR^(c)R^(d), C(O)OR^(a),OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)(O)R^(b),NR^(c)(O)OR^(a), NR^(c)C(O)NR^(c)R^(d), C(═NR^(e))R^(b),C(═NR^(e))NR^(c)R^(d), NR^(c)C(═NR^(e))NR^(c)R^(d), NR^(c)S(O)R^(b),NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b), S(O)NR^(c)R^(d),S(O)₂R^(b), and S(O)₂NR^(c)R^(d);

A is selected from Formulas [aa], [bb], and [cc]:

rings B and C in Formula [aa] together form a fused bicyclicheterocycle, wherein ring B is a six-membered aromatic ring selectedfrom phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, andtriazinyl, wherein ring C is a 5- or 6-membered carbocycle or a 5- or6-membered heterocycle, wherein 0, 1, or 2 ring-forming carbon ornitrogen atoms in ring C can be substituted by oxo, and wherein thefused bicyclic heterocycle comprising rings B and C is attached to L inFormula I via a ring atom in ring B;

Q¹, Q², and Q³ are each independently selected from N and CH, wherein atleast one of Q¹, Q², and Q³ is CH;

each R^(X) is a substituent on ring B and is independently selected fromhalo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, and C₁₋₄ cyanoalkyl;

each R^(Y) is a substituent on ring C and is independently selected fromC₁₋₆ alkyl, C₁₋₆ haloalkyl, Cy¹, OR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1),C(O)OR^(a1), C(═NR^(e1))R^(b1), NR^(e1))NR^(c1)R^(d1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1), wherein saidC₁₋₆ alkyl, is optionally substituted with 1, 2, 3, 4, or 5 substituentsindependently selected from R^(Ya);

each R^(Ya) is independently selected from Cy¹, halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a1), SR^(a1),C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1),OC(O)NR^(c1)R^(d1), C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)S(O)R^(b1),NR^(c1)(O)₂R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1), wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl of R^(Ya) are each optionallysubstituted with 1, 2, or 3 substituents independently selected fromCy¹, halo, CN, NO₂, OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1),C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1), C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)S(O)R^(b1),NR^(c1)S(O)₂R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1);

each R^(A) is independently selected from halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, Cy², CN, NO₂, OR^(a2), SR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2),NR^(c2)R^(d2), NR^(c2)C(O)R^(b2), NR^(c2)C(O)OR^(a2),NR^(c2)C(O)NR^(c2)R^(d2), C(═NR^(e2))R^(b2), C(═NR^(e2))NR^(c2)R^(d2),NR^(c2)C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2),NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2),and S(O)₂NR^(c2)R^(d2); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl are each optionally substituted with 1, 2, 3, 4, or 5substituents independently selected from R^(AZ);

each R^(AZ) is independently selected from Cy², halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a2), SR^(a2),C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), C(═NR^(e2))NR^(c2)R^(d2),NR^(c2)C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)S(O)R^(b2),NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2), wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl of R^(AZ) are each optionallysubstituted with 1, 2, or 3 substituents independently selected fromCy², halo, CN, NO₂, OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2),C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2), C(═NR^(e2))NR^(c2)R^(d2),NR^(c2)C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)S(O)R^(b2),NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2);

R^(B1) is H, C₁₋₆ alkyl, Cy³, C(O)R^(b3), C(O)NR^(c3)R^(d3),C(O)OR^(a3), C(═NR^(e3))R^(b3), or C(═NR^(e3))NR^(c3)R^(d3); whereinsaid C₁₋₆ alkyl, is optionally substituted with 1, 2, 3, 4, or 5substituents independently selected from R^(BZ);

each R^(BZ) is independently selected from Cy³, halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a3), SR^(a3),C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3),OC(O)NR^(c3)R^(d3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)S(O)R^(b3),NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3), wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl of R^(BZ) are each optionallysubstituted with 1, 2, or 3 substituents independently selected fromCy³, halo, CN, NO₂, OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3),c(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)S(O)R^(b3),NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3);

each R^(B2) is independently selected from halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, Cy³, CN, NO₂, OR^(a3), SR^(a3), C(O)R^(b3),C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3),NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3),NR^(c3)C(O)NR^(c3)R^(d3), C(═NR^(e3))R^(b3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)S(O)R^(b3), NR^(c3)S(O)₂R^(b3),NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3),and S(O)₂NR^(c3)R^(d3); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl are each optionally substituted with 1, 2, 3, 4, or 5substituents independently selected from R^(BZ);

R¹, R², R⁴, and R⁵ are each independently selected from halo, C₁₋₄alkyl, C₁₋₄ haloalkyl, CN, OR^(a4), SR^(a4), C(O)NR^(c4)R^(d4),NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)S(O)R^(b4), NR^(c4)S(O)₂R^(b4),S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4);wherein said C₁₋₄ alkyl is optionally substituted with 1, 2, or 3substituents independently selected from halo, CN, OR^(a4), SR^(a4),C(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)S(O)R^(b4),NR^(c4)S(O)₂R^(b4), S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4), andS(O)₂NR^(c4)R^(d4);

R³ is H, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, CN, OR^(a4), SR^(a4),C(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)S(O)R^(b4),NR^(c4)S(O)₂R^(b4), S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4), andS(O)₂NR^(c4)R^(d4); wherein said C₁₋₄ alkyl is optionally substitutedwith 1, 2, or 3 substituents independently selected from halo, CN,OR^(a4), SR^(a4), C(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)S(O)R^(b4), NR^(c4)S(O)₂R^(b4), S(O)R^(b4), S(O)NR^(c4)R^(d4),S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4);

R⁶, R⁷, and R⁸ are each independently selected from H, halo, C₁₋₄ alkyl,C₁₋₄ haloalkyl, and C₁₋₄cyanoalkyl;

Cy¹, Cy², and Cy³ are each independently selected from C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,each of which is optionally substituted by 1, 2, 3, 4, or 5 substituentsindependently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, CN, NO₂, OR^(a5), SR^(a5),C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5),OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)OR^(a5), NR^(c5)C(O)NR^(c5)R^(d5), C(═NR^(e5))R^(b5),C(═NR^(e5))NR^(c5)R^(d5), NR^(c5)C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)S(O)R^(b5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5),S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are eachoptionally substituted with 1, 2, or 3 substituents independentlyselected from halo, C₁₋₄ haloalkyl, CN, NO₂, OR^(a5), SR^(a5),C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5),OC(O)NR^(c5)R^(d5), C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)C(═NR^(e5))NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)OR^(a5), NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)S(O)R^(b5),NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), S(O)R^(b5),S(O)NR^(c5)R^(d5), S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5);

each R^(a), R^(b), R^(c), R^(d), R^(a1), R^(b1), R^(c1), R^(d1), R^(a2),R^(b2), R^(c2), R^(d2), R^(a3), R^(b3), R^(c3), R^(d3), R^(a5), R^(b5),R^(c5), and R^(d5) is independently selected from H, C₁₋₆ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, (5-10 memberedheteroaryl)-C₁₋₄ alkyl, or (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, (5-10 memberedheteroaryl)-C₁₋₄ alkyl, and (4-10 membered heterocycloalkyl)-C₁₋₄ alkylis optionally substituted with 1, 2, 3, 4, or 5 substituentsindependently selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl, halo, CN,OR^(a6), SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6),OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6), C(═NR^(e6))NR^(c6)R^(d6),NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), S(O)R^(b6), S(O)NR^(c6)R^(d6),S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6), NR^(c6)S(O)₂NR^(c6)R^(d6), andS(O)₂NR^(c6)R^(d6);

each R^(a4), R^(b4), R^(c4), and R^(d4) is independently selected fromH, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ hydroxyalkyl, and C₁₋₄ cyanoalkyl;

or any R^(c) and R^(d) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆ haloalkyl,halo, CN, OR^(a6), SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6),OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6), C(═NR^(e6))NR^(c6)R^(d6),NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), S(O)R^(b6), S(O)NR^(c6)R^(d6),S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6), NR^(c6)S(O)₂NR^(c6)R^(d6), andS(O)₂NR^(c6)R^(d6), wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl areoptionally substituted by 1, 2, or 3 substituents independently selectedfrom halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, CN, OR^(a6),SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6), OC(O)R^(b6),OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6), C(═NR^(e6))NR^(c6)R^(d6),NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), S(O)R^(b6), S(O)NR^(c6)R^(d6),S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6), NR^(c6)S(O)₂NR^(c6)R^(d6), andS(O)₂NR^(c6)R^(d6);

or any R^(c1) and R^(d1) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 3-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆haloalkyl,halo, CN, OR^(a6), SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6),OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6), C(═NR^(e6))NR^(c6)R^(d6),NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), S(O)R^(b6), S(O)NR^(c6)R^(d6),S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6), NR^(c6)S(O)₂NR^(c6)R^(d6), andS(O)₂NR^(c6)R^(d6), wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl areoptionally substituted by 1, 2, or 3 substituents independently selectedfrom halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ cyanoalkyl, CN, OR^(a6),SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6), OC(O)R^(b6),OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6), C(═NR^(e6))NR^(c6)R^(d6),NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), S(O)R^(b6), S(O)NR^(c6)R^(d6),S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6), NR^(c6)S(O)₂NR^(c6)R^(d6), andS(O)₂NR^(c6)R^(d6);

or any R^(c2) and R^(d2) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl,C₁₋₆haloalkyl, halo, CN, OR^(a6), SR^(a6), C(O)R^(b6),C(O)NR^(c6)R^(d6), C(O)OR^(a6), OC(O)R^(b6), OC(O)NR^(c6)R^(d6),NR^(c6)R^(d6), NR^(c6)C(O)R^(b6), NR^(c6)C(O)NR^(c6)R^(d6),NR^(c6)C(O)OR^(a6), C(═NR^(e6))NR^(c6)R^(d6),NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), S(O)R^(b6), S(O)NR^(c6)R^(d6),S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6), NR^(c6)S(O)₂NR^(c6)R^(d6), andS(O)₂NR^(c6)R^(d6), wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl areoptionally substituted by 1, 2, or 3 substituents independently selectedfrom halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ cyanoalkyl, CN, OR^(a6),SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6), OC(O)R^(b6),OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6), C(═NR^(e6))NR^(c6)R^(d6),NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), S(O)R^(b6), S(O)NR^(c6)R^(d6),S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6), NR^(c6)S(O)₂NR^(c6)R^(d6), andS(O)₂NR^(c6)R^(d6);

or any R^(c3) and R^(d3) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆haloalkyl,halo, CN, OR^(a6), SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6),OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6), C(═NR^(e6))NR^(c6)R^(d6),NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), S(O)R^(b6), S(O)NR^(c6)R^(d6),S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6), NR^(c6)S(O)₂NR^(c6)R^(d6), andS(O)₂NR^(c6)R^(d6), wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl areoptionally substituted by 1, 2, or 3 substituents independently selectedfrom halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ cyanoalkyl, CN, OR^(a6),SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6), OC(O)R^(b6),OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6), C(═NR^(e6))NR^(c6)R^(d6),NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), S(O)R^(b6), S(O)NR^(c6)R^(d6),S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6), NR^(c6)S(O)₂NR^(c6)R^(d6), andS(O)₂NR^(c6)R^(d6);

or any R^(c5) and R^(d5) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆ haloalkyl,halo, CN, OR^(a6), SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6),OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6), C(═NR^(e6))NR^(c6)R^(d6),NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), S(O)R^(b6), S(O)NR^(c6)R^(d6),S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6), NR^(c6)S(O)₂NR^(c6)R^(d6), andS(O)₂NR^(c6)R^(d6), wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl areoptionally substituted by 1, 2, or 3 substituents independently selectedfrom halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ cyanoalkyl, CN, OR^(a6),SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6), OC(O)R^(b6),OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6), C(═NR^(e6))NR^(c6)R^(d6),NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), S(O)R^(b6), S(O)NR^(c6)R^(d6),S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6), NR^(c6)S(O)₂NR^(c6)R^(d6), andS(O)₂NR^(c6)R^(d6);

each R^(a6), R^(b6), R^(c6), and R^(d6) is independently selected fromH, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl, whereinsaid C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl, is optionallysubstituted with 1, 2, or 3 substituents independently selected from OH,CN, amino, halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy;

or any R^(c6) and R^(d6) together with the N atom to which they areattached form a 3-, 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from OH, CN, amino, halo, C₁₋₆ alkyl, C₁₋₄ alkoxy, C₁₋₄alkylthio, C₁₋₄ alkylamino, di(C₁₋₄alkyl)amino, C₁₋₄ haloalkyl, and C₁₋₄haloalkoxy; and

each R^(e), R^(e1), R^(e2), R^(e3), R^(e5), and R^(e6) is independentlyselected from H, C₁₋₄ alkyl, and CN;

n1 is 0, 1, 2, 3, 4, or 5;

n2 is 0, 1, or 2;

p is 0, 1, 2, or 3; and

q is 0, 1, 2, or 3.

In some embodiments: W is CR⁶; Y is N; and Z is N.

In some embodiments: W is CR⁶; Y is N; and Z is CR⁸.

In some embodiments: W is CR⁶; Y is CR⁷; and Z is N.

In some embodiments: W is N; Y is CR⁷; and Z is CR⁸.

In some embodiments, L is absent.

In some embodiments, L is selected from C₂₋₆ alkenylene, C₃₋₆heteroalkenylene, C₂₋₆ alkynylene, and C₃₋₆ heteroalkynylene, whereinsaid C₂₋₆ alkenylene, C₃₋₆ heteroalkenylene, C₂₋₆ alkynylene, and C₃₋₆heteroalkynylene are each optionally substituted with 1, 2, or 3substituents independently selected from halo, CN, NO₂, OR^(a), C₁₋₄alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, C(O)NR^(c)R^(d), C(O)OR^(a),OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)(O)R^(b),NR^(c)(O)OR^(a), NR^(c)C(O)NR^(c)R^(d), C(═NR^(e))R^(b),C(═NR^(e))NR^(c)R^(d), NR^(c)C(═NR^(e))NR^(c)R^(d), NR^(c)S(O)R^(b),NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b), S(O)NR^(c)R^(d),S(O)₂R^(b), and S(O)₂NR^(c)R^(d).

In some embodiments, L is selected from C₂₋₆ alkenylene and C₂₋₆alkynylene, wherein said C₂₋₆ alkenylene and C₂₋₆ alkynylene are eachoptionally substituted with 1, 2, or 3 substituents independentlyselected from halo, CN, NO₂, OR^(a), C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄cyanoalkyl, C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d),NR^(c)R^(d), NR^(c)(O)R^(b), NR^(c)(O)OR^(a), NR^(c)C(O)NR^(c)R^(d),C(═NR^(e))R^(b), C(═NR^(e))NR^(c)R^(d), NR^(c)C(═NR^(e))NR^(c)R^(d),NR^(c)S(O)R^(b), NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), and S(O)₂NR^(c)R^(d).

In some embodiments, L is selected from C₂₋₆ alkenylene and C₂₋₆alkynylene.

In some embodiments, R³ is H.

In some embodiments, R¹, R², R⁴, and R⁵ are each independently selectedfrom halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN, and OR^(a4).

In some embodiments, R¹, R², R⁴, and R⁵ are each independently selectedfrom F, Cl, and methoxy.

In some embodiments, R¹ and R⁵ are each independently selected from Fand Cl, and R² and R⁴ are each methoxy.

In some embodiments, R⁶, R⁷, and R⁸ are each independently selected fromH and halo.

In some embodiments, R⁶, R⁷, and R⁸ are each H.

In some embodiments, A is a group represented by Formula [aa].

In some embodiments, Ring B is phenyl or pyridyl.

In some embodiments, Ring C is a 5-membered carbocycle or a 5-memberedheterocycle.

In some embodiments, Ring C is a 6-membered carbocycle or a 6-memberedheterocycle.

In some embodiments, Formula [aa] is a group having a structure selectedfrom:

In some embodiments, each R^(Y) is independently selected from C₁₋₆alkyl, C₁₋₆ haloalkyl, Cy¹, C(O)NR^(c1)R^(d1), C(O)OR^(a1), andS(O)₂R^(b1), wherein said C₁₋₆ alkyl is optionally substituted withhalo, CN, OR^(a1), NR^(c1)R^(d1), or Cy¹.

In some embodiments, each R^(Y) is independently selected from C₁₋₆alkyl, Cy¹, C(O)NR^(c1)R^(d1), C(O)OR^(a1), and S(O)₂R^(b1), whereinsaid C₁₋₆ alkyl is optionally substituted with halo, OR^(a1),NR^(c1)R^(d1), or Cy¹.

In some embodiments:

each R^(Y) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,Cy¹, C(O)NR^(c1)R^(d1), C(O)OR^(a1), and S(O)₂R^(b1), wherein said C₁₋₆alkyl is optionally substituted with halo, —CN, OR^(a1), NR^(c1)R^(d1),or Cy¹;

Cy¹ is C₃₋₆ cycloalkyl or 4-7 membered heterocycloalkyl, each of whichis optionally substituted by 1 or 2 substituents independently selectedfrom halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, hydroxy or C₁₋₆ alkoxy; and

each R^(a1), R^(b1), R^(c1), and R^(d1) is independently selected fromH, C₁₋₆ alkyl, and C₁₋₄ haloalkyl;

or any R^(c1) and R^(d1) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with C₁₋₆ alkyl.

In some embodiments, each R^(Y) is independently selected fromdimethylaminocarbonyl, (4-methylpiperazinyl)carbonyl, methyl, ethyl,2-propyl, methylsulfonyl, 4-hydroxycyclohexyl, cyclopropyl,methoxyethyl, tetrahydro-2H-pyran-4-yl, 2,2,2-trifluoroethyl,2-hydroxy-1-methylethyl, 2-hydroxypropyl, 1-methylpiperidin-4-yl,dimethylaminoethyl, (1-methylpyrolidin-2-yl)ethyl, 1-cyanoethyl, andmethoxycarbonyl.

In some embodiments, p is 0, 1, or 2.

In some embodiments, p is 0 or 1.

In some embodiments, p is 1.

In some embodiments, each R^(X) is halo.

In some embodiments, each R^(X) if F.

In some embodiments, q is 0.

In some embodiments, A is a group represented by Formula [bb].

In some embodiments, Q¹, Q², and Q³ are each CH.

In some embodiments, Q¹ is N and Q², and Q³ are each CH.

In some embodiments, Q¹ and Q² are both CH and Q³ is N.

In some embodiments, each R^(A) is independently selected from halo,C₁₋₆ alkyl, Cy², and OR^(a2); wherein said C₁₋₆ alkyl is optionallysubstituted with 1, 2, or 3 substituents independently selected from R.

In some embodiments:

each R^(A) is independently selected from halo, C₁₋₆ alkyl, Cy², andOR^(a2), wherein said C₁₋₆ alkyl is optionally substituted with 1, 2, or3 substituents independently selected from R^(AZ);

Cy² is 4-7 membered heterocycloalkyl optionally substituted C₁₋₆ alkyl;

R^(a2) is H or C₁₋₆ alkyl, wherein said C₁₋₆ alkyl is optionallysubstituted with 1 or 2 substituents independently selected from halo,CN, OH, C₁₋₄ alkyl, —C(O)NH₂, —C(O)NH(C₁₋₄ alkyl), —C(O)N(C₁₋₄ alkyl)₂,—NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂; and

R^(AZ) is independently selected from halo, CN, OH, C₁₋₄ alkyl,—C(O)NH₂, —C(O)NH(C₁₋₄ alkyl), —C(O)N(C₁₋₄ alkyl)₂, —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄ alkyl)₂.

In some embodiments, each R^(A) is independently selected from methoxy,4-methylpiperazinyl, dimethylaminoethyloxy, methyl,dimethylaminocarbonylmethyloxy, fluoro, and2-hydroxy-N,N-dimethylacetamide.

In some embodiments, n1 is 0, 1, or 2.

In some embodiments, A is a group represented by Formula [cc].

In some embodiments, A is a group represented by Formula [cc1]:

In some embodiments, R^(B1) is C₁₋₆ alkyl optionally substituted with 1or 2 substituents independently selected from R^(BZ).

In some embodiments:

R^(B1) is C₁₋₆ alkyl optionally substituted with 1 or 2 substituentsindependently selected from R^(BZ);

R^(BZ) is independently selected from halo, CN, —OH, C₁₋₄ alkoxy, andC(O)NR^(c3)R^(d3); and

each R^(c3) and R^(d3) is independently selected from H, C₁₋₆ alkyl,C₁₋₄haloalkyl, C₁₋₃ alkoxy-C₁₋₆ alkyl, C₃₋₆ cycloalkyl,1-methylpiperidinyl, and tetrahydro-2H-pyranyl;

or any R^(c3) and R^(d3) together with the N atom to which they areattached form a 4-, 5-, or 6-membered heterocycloalkyl group optionallysubstituted with 1 or 2 substituents independently selected from C₁₋₄alkyl, halo, CN, —OH, C₁₋₄ alkoxy, —NH₂, —NH(C₁₋₄ alkyl), and —N(C₁₋₄alkyl)₂.

In some embodiments, R^(B1) is 1-cyanoethyl, methyl,methylaminocarbonylmethyl, dimethylaminocarbonylmethyl,cyclopropylaminocarbonylmethyl, (3-hydroxyazeditinyl)carbonylmethyl,morpholinocarbonylmethyl, (4-methylpyrazinyl)carbonylmethyl,(1-methylpiperidin-4-yl)aminocarbonylmethyl,(3-hydroxypyrolidinyl)carbonylmethyl,(3-dimethylaminopyrolidinyl)carbonylmethyl,(3-methoxypyrolidinyl)carbonylmethyl, methoxyethylaminocarbonylmethyl,(3-cyanopyrolidinyl)carbonylmethyl, (3-fluoropyrolidinyl)carbonylmethyl,hydroxyethyl, (tetrahydro-2H-pyran-2-yl)oxyethyl, 2-hydroxypropyl,3-hydroxypropyl, or 2-hydroxyethyl.

In some embodiments, each R^(BZ) is independently selected from CN,OR^(a3), and C(O)NR^(c3)R^(d3).

In some embodiments, n2 is 0.

In some embodiments, the compounds of the invention have Formula IIa,IIb, IIc, or IId:

wherein R¹ and R⁵ are independently selected from F and Cl.

It is further appreciated that certain features of the invention, whichare, for clarity, described in the context of separate embodiments, canalso be provided in combination in a single embodiment. Conversely,various features of the invention which are, for brevity, described inthe context of a single embodiment, can also be provided separately orin any suitable subcombination.

At various places in the present specification, substituents ofcompounds of the invention are disclosed in groups or in ranges. It isspecifically intended that the invention include each and everyindividual subcombination of the members of such groups and ranges. Forexample, the term “C₁₋₆ alkyl” is specifically intended to individuallydisclose methyl, ethyl, C₃ alkyl, C₄ alkyl, C₅ alkyl, and C₆ alkyl.

At various places in the present specification various aryl, heteroaryl,cycloalkyl, and heterocycloalkyl rings are described. Unless otherwisespecified, these rings can be attached to the rest of the molecule atany ring member as permitted by valency. For example, the term“pyridyl,” “pyridinyl,” or “a pyridine ring” may refer to apyridin-2-yl, pyridin-3-yl, or pyridin-4-yl ring.

The term “n-membered” where n is an integer typically describes thenumber of ring-forming atoms in a moiety where the number ofring-forming atoms is n. For example, piperidinyl is an example of a6-membered heterocycloalkyl ring, pyrazolyl is an example of a5-membered heteroaryl ring, pyridyl is an example of a 6-memberedheteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a10-membered cycloalkyl group.

For compounds of the invention in which a variable appears more thanonce, each variable can be a different moiety independently selectedfrom the group defining the variable. For example, where a structure isdescribed having two R groups that are simultaneously present on thesame compound, the two R groups can represent different moietiesindependently selected from the group defined for R.

As used herein, the phrase “optionally substituted” means unsubstitutedor substituted.

As used herein, the term “substituted” means that a hydrogen atom isreplaced by a non-hydrogen group. It is to be understood thatsubstitution at a given atom is limited by valency.

As used herein, the term “C_(i-j)”, where i and j are integers, employedin combination with a chemical group, designates a range of the numberof carbon atoms in the chemical group with i-j defining the range. Forexample, C₁₋₆ alkyl refers to an alkyl group having 1, 2, 3, 4, 5, or 6carbon atoms.

As used herein, the term “alkyl”, employed alone or in combination withother terms, refers to a saturated hydrocarbon group that may bestraight-chain or branched. In some embodiments, the alkyl groupcontains 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of alkylmoieties include, but are not limited to, chemical groups such asmethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, n-pentyl, 2-methyl-1-butyl, 3-pentyl, n-hexyl,1,2,2-trimethylpropyl, and the like. In some embodiments, the alkylgroup is methyl, ethyl, or propyl.

As used herein, “alkenyl”, employed alone or in combination with otherterms, refers to an alkyl group having one or more carbon-carbon doublebonds. In some embodiments, the alkenyl moiety contains 2 to 6 or 2 to 4carbon atoms. Example alkenyl groups include, but are not limited to,ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like.

As used herein, “alkenylene”, refers to a linking alkenyl group.

As used herein, “alkynyl”, employed alone or in combination with otherterms, refers to an alkyl group having one or more carbon-carbon triplebonds. Example alkynyl groups include, but are not limited to, ethynyl,propyn-1-yl, propyn-2-yl, and the like. In some embodiments, the alkynylmoiety contains 2 to 6 or 2 to 4 carbon atoms.

As used herein, “alkynylene” refers to a linking alkynyl group.

As used herein, “heteroalkenylene” refers to an alkenylene group whereina methylene group in the alkenylene group is replaced with O, S, C(O),S(O), S(O)₂, NR, C(O)—O, C(O)—NR, S(O)—NR, or S(O)₂—NR group, wherein Ris H, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ hydroxyalkyl, cyano-C₁₋₄ alkyl,cyclopropyl, or cyclopropyl-C₁₋₄ alkyl.

As used herein, “heteroalkynylene” refers to an alkynylene group whereina methylene group in the alkynylene group is replaced with O, S, C(O),S(O), S(O)₂, NR, C(O)—O, C(O)—NR, S(O)—NR, or S(O)₂—NR group, wherein Ris H, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ hydroxyalkyl, cyano-C₁₋₄ alkyl,cyclopropyl, or cyclopropyl-C₁₋₄ alkyl. An example heteroalkynylenegroup is —C≡C—CH₂—NH—C(O)—.

As used herein, “halo” or “halogen”, employed alone or in combinationwith other terms, includes fluoro, chloro, bromo, and iodo. In someembodiments, halo is F or Cl.

As used herein, the term “haloalkyl”, employed alone or in combinationwith other terms, refers to an alkyl group having up to the full valencyof halogen atom substituents, which may either be the same or different.In some embodiments, the halogen atoms are fluoro atoms. In someembodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. Examplehaloalkyl groups include CF₃, C₂F₅, CHF₂, CCl₃, CHCl₂, C₂Cl₅, and thelike.

As used herein, the term “cyanoalkyl”, employed alone or in combinationwith other terms, refers to an alkyl group substituted by a cyano group.

As used herein, the term “alkoxy”, employed alone or in combination withother terms, refers to a group of formula —O-alkyl. Example alkoxygroups include methoxy, ethoxy, propoxy (e.g., n-propoxy andisopropoxy), t-butoxy, and the like. In some embodiments, the alkylgroup has 1 to 6 or 1 to 4 carbon atoms.

As used herein, “haloalkoxy”, employed alone or in combination withother terms, refers to a group of formula —O-(haloalkyl). In someembodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. Anexample haloalkoxy group is —OCF₃.

As used herein, “amino”, employed alone or in combination with otherterms, refers to NH₂.

As used herein, the term “alkylamino”, employed alone or in combinationwith other terms, refers to a group of formula —). In some embodiments,the alkylamino group has 1 to 6 or 1 to 4 carbon atoms. Examplealkylamino groups include methylamino, ethylamino, propylamino (e.g.,n-propylamino and isopropylamino), and the like.

As used herein, the term “dialkylamino”, employed alone or incombination with other terms, refers to a group of formula —N(alkyl)₂.Example dialkylamino groups include dimethylamino, diethylamino,dipropylamino (e.g., di(n-propyl)amino and di(isopropyl)amino), and thelike. In some embodiments, each alkyl group independently has 1 to 6 or1 to 4 carbon atoms.

As used herein, the term “alkylthio”, employed alone or in combinationwith other terms, refers to a group of formula —S-alkyl. In someembodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

As used herein, the term “cycloalkyl”, employed alone or in combinationwith other terms, refers to a non-aromatic cyclic hydrocarbon includingcyclized alkyl and alkenyl groups. Cycloalkyl groups can include mono-or polycyclic (e.g., having 2, 3, or 4 fused, bridged, or spiro rings)ring systems. Also included in the definition of cycloalkyl are moietiesthat have one or more aromatic rings (e.g., aryl or heteroaryl rings)fused (i.e., having a bond in common with) to the cycloalkyl ring, forexample, benzo derivatives of cyclopentane, cyclohexene, cyclohexane,and the like, or pyrido derivatives of cyclopentane or cyclohexane.Ring-forming carbon atoms of a cycloalkyl group can be optionallysubstituted by oxo. Cycloalkyl groups also include cycloalkylidenes. Theterm “cycloalkyl” also includes bridgehead cycloalkyl groups (e.g.,non-aromatic cyclic hydrocarbon moieties containing at least onebridgehead carbon, such as admantan-1-yl) and spirocycloalkyl groups(e.g., non-aromatic hydrocarbon moieties containing at least two ringsfused at a single carbon atom, such as spiro[2.5]octane and the like).In some embodiments, the cycloalkyl group has 3 to 10 ring members, or 3to 7 ring members. In some embodiments, the cycloalkyl group ismonocyclic or bicyclic. In some embodiments, the cycloalkyl group ismonocyclic. In some embodiments, the cycloalkyl group is a C₃₋₇monocyclic cycloalkyl group. Example cycloalkyl groups includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl,norbornyl, norpinyl, norcarnyl, tetrahydronaphthalenyl,octahydronaphthalenyl, indanyl, and the like. In some embodiments, thecycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

As used herein, the term “cycloalkylalkyl”, employed alone or incombination with other terms, refers to a group of formulacycloalkyl-alkyl-. In some embodiments, the alkyl portion has 1 to 4, 1to 3, 1 to 2, or 1 carbon atom(s). In some embodiments, the alkylportion is methylene. In some embodiments, the cycloalkyl portion has 3to 10 ring members or 3 to 7 ring members. In some embodiments, thecycloalkyl group is monocyclic or bicyclic. In some embodiments, thecycloalkyl portion is monocyclic. In some embodiments, the cycloalkylportion is a C₃₋₇ monocyclic cycloalkyl group.

As used herein, the term “heterocycloalkyl”, employed alone or incombination with other terms, refers to a non-aromatic ring or ringsystem, which may optionally contain one or more alkenylene oralkynylene groups as part of the ring structure, which has at least oneheteroatom ring member independently selected from nitrogen, sulfur,oxygen, and phosphorus. Heterocycloalkyl groups can include mono- orpolycyclic (e.g., having 2, 3 or 4 fused, bridged, or spiro rings) ringsystems. In some embodiments, the heterocycloalkyl group is a monocyclicor bicyclic group having 1, 2, 3, or 4 heteroatoms independentlyselected from nitrogen, sulfur and oxygen. Also included in thedefinition of heterocycloalkyl are moieties that have one or morearomatic rings (e.g., aryl or heteroaryl rings) fused (i.e., having abond in common with) to the non-aromatic heterocycloalkyl ring, forexample, 1,2,3,4-tetrahydro-quinoline and the like. Heterocycloalkylgroups can also include bridgehead heterocycloalkyl groups (e.g., aheterocycloalkyl moiety containing at least one bridgehead atom, such asazaadmantan-1-yl and the like) and spiroheterocycloalkyl groups (e.g., aheterocycloalkyl moiety containing at least two rings fused at a singleatom, such as [1,4-dioxa-8-aza-spiro[4.5]decan-N-yl] and the like). Insome embodiments, the heterocycloalkyl group has 3 to 10 ring-formingatoms, or about 3 to 8 ring forming atoms. In some embodiments, theheterocycloalkyl group has 2 to 20 carbon atoms, 2 to 15 carbon atoms, 2to 10 carbon atoms, or about 2 to 8 carbon atoms. In some embodiments,the heterocycloalkyl group has 1 to 5 heteroatoms, 1 to 4 heteroatoms, 1to 3 heteroatoms, or 1 to 2 heteroatoms. The carbon atoms or heteroatomsin the ring(s) of the heterocycloalkyl group can be oxidized to form acarbonyl, an N-oxide, or a sulfonyl group (or other oxidized linkage) ora nitrogen atom can be quaternized. In some embodiments, theheterocycloalkyl portion is a C₂₋₇ monocyclic heterocycloalkyl group. Insome embodiments, the heterocycloalkyl group is a morpholine ring,pyrrolidine ring, piperazine ring, piperidine ring, tetrahydropyranring, tetrahyropyridine, azetidine ring, tetrahydrofuran ring, indolinering, pyrrolidinone ring, piperazinone ring, piperidinone ring, orindolinone ring.

As used herein, the term “heterocycloalkylalkyl”, employed alone or incombination with other terms, refers to a group of formulaheterocycloalkyl-alkyl-. In some embodiments, the alkyl portion has 1 to4, 1 to 3, 1 to 2, or 1 carbon atom(s). In some embodiments, the alkylportion is methylene. In some embodiments, the heterocycloalkyl portionhas 3 to 10 ring members or 3 to 7 ring members. In some embodiments,the heterocycloalkyl group is monocyclic or bicyclic. In someembodiments, the heterocycloalkyl portion is monocyclic. In someembodiments, the heterocycloalkyl portion is a C₂₋₇ monocyclicheterocycloalkyl group.

As used herein, the term “aryl”, employed alone or in combination withother terms, refers to a monocyclic or polycyclic (e.g., having 2 fusedrings) aromatic hydrocarbon moiety, such as, but not limited to, phenyl,1-naphthyl, 2-naphthyl, and the like. In some embodiments, aryl groupshave from 6 to 10 carbon atoms or 6 carbon atoms. In some embodiments,the aryl group is a monocyclic or bicyclic group. In some embodiments,the aryl group is phenyl or naphthyl.

As used herein, the term “arylalkyl”, employed alone or in combinationwith other terms, refers to a group of formula aryl-alkyl-. In someembodiments, the alkyl portion has 1 to 4, 1 to 3, 1 to 2, or 1 carbonatom(s). In some embodiments, the alkyl portion is methylene. In someembodiments, the aryl portion is phenyl. In some embodiments, the arylgroup is a monocyclic or bicyclic group. In some embodiments, thearylalkyl group is benzyl.

As used herein, the term “heteroaryl”, employed alone or in combinationwith other terms, refers to a monocyclic or polycyclic (e.g., having 2or 3 fused rings) aromatic hydrocarbon moiety, having one or moreheteroatom ring members independently selected from nitrogen, sulfur andoxygen. In some embodiments, the heteroaryl group is a monocyclic orbicyclic group having 1, 2, 3, or 4 heteroatoms independently selectedfrom nitrogen, sulfur and oxygen. Example heteroaryl groups include, butare not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,triazinyl, furyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl,oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, benzodioxolyl,isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl,1,2,4-thiadiazolyl, isothiazolyl, purinyl, carbazolyl, benzimidazolyl,pyrrolyl, azolyl, quinolinyl, isoquinolinyl, benzisoxazolyl,imidazo[1,2-b]thiazolyl, pyridopyrazinyl, or the like. The carbon atomsor heteroatoms in the ring(s) of the heteroaryl group can be oxidized toform a carbonyl, an N-oxide, or a sulfonyl group (or other oxidizedlinkage) or a nitrogen atom can be quaternized, provided the aromaticnature of the ring is preserved. In some embodiments, the heteroarylgroup has from 3 to 10 carbon atoms, from 3 to 8 carbon atoms, from 3 to5 carbon atoms, from 1 to 5 carbon atoms, or from 5 to 10 carbon atoms.In some embodiments, the heteroaryl group contains 3 to 14, 4 to 12, 4to 8, 9 to 10, or 5 to 6 ring-forming atoms. In some embodiments, theheteroaryl group has 1 to 4, 1 to 3, or 1 to 2 heteroatoms.

As used herein, the term “heteroarylalkyl”, employed alone or incombination with other terms, refers to a group of formulaheteroaryl-alkyl-. In some embodiments, the alkyl portion has 1 to 4, 1to 3, 1 to 2, or 1 carbon atom(s). In some embodiments, the alkylportion is methylene. In some embodiments, the heteroaryl portion is amonocyclic or bicyclic group having 1, 2, 3, or 4 heteroatomsindependently selected from nitrogen, sulfur and oxygen. In someembodiments, the heteroaryl portion has 5 to 10 carbon atoms.

As used herein, the term “carbocycle” refers to an aryl group or acycloalkyl group.

As used herein, the term “heterocycle” refers to a heteroaryl group or aheterocycloalkyl group.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereomers, are intended unless otherwise indicated. Compounds of thepresent invention that contain asymmetrically substituted carbon atomscan be isolated in optically active or racemic forms. Methods on how toprepare optically active forms from optically inactive startingmaterials are known in the art, such as by resolution of racemicmixtures or by stereoselective synthesis. Many geometric isomers ofolefins, C═N double bonds, and the like can also be present in thecompounds described herein, and all such stable isomers are contemplatedin the present invention. Cis and trans geometric isomers of thecompounds of the present invention are described and may be isolated asa mixture of isomers or as separated isomeric forms.

Resolution of racemic mixtures of compounds can be carried out by any ofnumerous methods known in the art. An example method includes fractionalrecrystallizaion using a chiral resolving acid which is an opticallyactive, salt-forming organic acid. Suitable resolving agents forfractional recrystallization methods are, for example, optically activeacids, such as the D and L forms of tartaric acid, diacetyltartaricacid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid orthe various optically active camphorsulfonic acids. Other resolvingagents suitable for fractional crystallization methods includestereoisomerically pure forms of methylbenzyl-amine (e.g., S and Rforms, or diastereomerically pure forms), 2-phenylglycinol,norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine,1,2-diaminocyclohexane, and the like. Resolution of racemic mixtures canalso be carried out by elution on a column packed with an opticallyactive resolving agent (e.g., dinitrobenzoylphenylglycine). Suitableelution solvent composition can be determined by one skilled in the art.

Compounds of the invention also include tautomeric forms. Tautomericforms result from the swapping of a single bond with an adjacent doublebond together with the concomitant migration of a proton. Tautomericforms include prototropic tautomers which are isomeric protonationstates having the same empirical formula and total charge. Exampleprototropic tautomers include ketone—enol pairs, amide—imidic acidpairs, lactam lactim pairs, enamine imine pairs, and annular forms wherea proton can occupy two or more positions of a heterocyclic system, forexample, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be inequilibrium or sterically locked into one form by appropriatesubstitution.

Compounds of the invention also include all isotopes of atoms occurringin the intermediates or final compounds. Isotopes include those atomshaving the same atomic number but different mass numbers. For example,isotopes of hydrogen include tritium and deuterium.

The term, “compound,” as used herein is meant to include allstereoisomers, geometric isomers, tautomers, and isotopes of thestructures depicted.

All compounds, and pharmaceutically acceptable salts thereof, can befound together with other substances such as water and solvents (e.g.,in the form of hydrates and solvates) or can be isolated.

In some embodiments, the compounds of the invention, or salts thereof,are substantially isolated. By “substantially isolated” is meant thatthe compound is at least partially or substantially separated from theenvironment in which it was formed or detected. Partial separation caninclude, for example, a composition enriched in the compounds of theinvention. Substantial separation can include compositions containing atleast about 50%, at least about 60%, at least about 70%, at least about80%, at least about 90%, at least about 95%, at least about 97%, or atleast about 99% by weight of the compounds of the invention, or saltthereof.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The present invention also includes pharmaceutically acceptable salts ofthe compounds described herein. As used herein, “pharmaceuticallyacceptable salts” refers to derivatives of the disclosed compoundswherein the parent compound is modified by converting an existing acidor base moiety to its salt form. Examples of pharmaceutically acceptablesalts include, but are not limited to, mineral or organic acid salts ofbasic residues such as amines; alkali or organic salts of acidicresidues such as carboxylic acids; and the like. The pharmaceuticallyacceptable salts of the present invention include the non-toxic salts ofthe parent compound formed, for example, from non-toxic inorganic ororganic acids. The pharmaceutically acceptable salts of the presentinvention can be synthesized from the parent compound which contains abasic or acidic moiety by conventional chemical methods. Generally, suchsalts can be prepared by reacting the free acid or base forms of thesecompounds with a stoichiometric amount of the appropriate base or acidin water or in an organic solvent, or in a mixture of the two;generally, non-aqueous media like ether, ethyl acetate, alcohols (e.g.,methanol, ethanol, iso-propanol, or butanol) or acetonitrile (ACN) arepreferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa.,1985, p. 1418 and Berge et al., Journal of Pharmaceutical Science, 66, 2(1977), each of which is incorporated herein by reference in itsentirety.

Synthesis

Compounds of the invention, including salts thereof, can be preparedusing known organic synthesis techniques and can be synthesizedaccording to any of numerous possible synthetic routes.

The reactions for preparing compounds of the invention can be carriedout in suitable solvents which can be readily selected by one of skillin the art of organic synthesis. Suitable solvents can be substantiallynonreactive with the starting materials (reactants), the intermediates,or products at the temperatures at which the reactions are carried out,e.g., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected by the skilled artisan.

Preparation of compounds of the invention can involve the protection anddeprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups, can bereadily determined by one skilled in the art. The chemistry ofprotecting groups can be found, for example, in P. G. M. Wuts and T. W.Greene, Greene's Protective Groups in Organic Synthesis, 4rd. Ed., Wiley& Sons, Inc., New Jersey (2007), which is incorporated herein byreference in its entirety.

Reactions can be monitored according to any suitable method known in theart. For example, product formation can be monitored by spectroscopicmeans, such as nuclear magnetic resonance spectroscopy (e.g., ¹H or¹³C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), ormass spectrometry, or by chromatography such as high performance liquidchromatography (HPLC) or thin layer chromatography.

Compounds of the invention can be prepared according to numerouspreparatory routes known in the literature. Example synthetic methodsfor preparing compounds of the invention are provided in the Schemesbelow.

A series of bicyclic pyrazole derivatives 6 can be prepared by themethods outlined in Scheme 1. Introduction of a protecting group PG(PG=THP, Boc or Cbz etc. . . . ) to compound 1 can provide thecorresponding compound 2. Suzuki coupling of 2 with a boronic acid orester ArB(OR′)₂ (R′=H or alkyl and Ar=aryl or heteroaryl, such as phenylsubstituted by R¹-R⁵ as in Formula I) can provide the pyrazolederivative 3. Removal of the protecting group in 3 (PG=THP or Boc) underacid conditions or (PG=Cbz) catalytic hydrogenation in the presence of acatalyst such as Pd/C or Pd(OH)₂/C affords the compound 4. Halogenationof the compound 4 with NIS (N-iodosuccinimide), NBS (N-bromosuccinimide)or NCS (N-chlorosuccinimide) can yield the corresponding pyrazole halide5 (X=I, Br or Cl), which can be further converted to the desiredpyrazole derivatives 6 by Suzuki coupling with a boronic acid or esterCyB(OR″)₂ (R″═H or alkyl, Cy=cyclic moiety such as A in Formula I).

Alternatively, a series of bicyclic pyrazole derivatives 3 can beprepared according to the procedure outlined in Scheme 2. The pyrazolederivatives 3 can be obtained by Stille coupling of ArX (X=I, Br, Cl orOTf) with tributyltin compound 7 can be prepared by palladium catalyzedreaction with Bu₃SnSnBu₃.

A series of aryl halide ArX (X=I, Br, Cl) 13 or aryl boronic acid orester ArB(OR′)₂ (R′=H or alkyl) derivatives 14 can be prepared accordingto the procedures described in Scheme 3. Displacement of fluorine incompound 8 with benzylamine provides the aniline 9 which can beconverted to bis-ether by reacting with a suitable sodium alkoxide (NaORwhere R is, e.g., methyl, alkyl). The following saponification canprovide acid 10. Decarboxylation of benzoic acid 10, followed byhydrogenation using Pd(OH)₂/C can afford aniline 12. Aniline derivatives12 can be converted to the corresponding halide ArX (X=I, Br, Cl) 13under standard Sandmeyer reaction conditions (e. g., aniline 13 reactswith sodium nitrite and hydrogen chloride to form an aryl diazoniumsalt, which was substituted by an halide ion in the presence of copper(I) bromide or potassium iodide to form the desired aryl halide). Thehalide 13 can be transferred to the corresponding aryl boronic acid orester 14.

A series of aniline derivatives 18 can be prepared according to theprocedures outlined in Scheme 4. Compound 16 can be obtained bytreatment of the aniline 15 (where R=methyl or alkyl) with aceticanhydride or acetyl chloride at low temperature. Treatment of compound16 with sulfuryl chloride can afford compound 17 which can be thenconverted to the aniline derivatives 18 by removal of the acetyl groupunder basic conditions.

A series of aniline derivatives 21 can be prepared according to theprocedures outlined in Scheme 5. Treatment of compound 16 withSelectfluor® can provide the desired mono-fluoride 19 which can then beconverted to compound 20 by treating with sulfuryl chloride. The acetylgroup of 20 can be removed under basic conditions to give the anilinederivatives 21.

A series of aryl boronic ester derivatives 23 can be prepared accordingto the procedures outlined in Scheme 6. Treatment of aryl boronic ester22 with sulfuryl chloride can afford the corresponding aryl boronicester 23.

A series of 1H-pyrazolo[3,4-d]pyrimidine derivatives 29 can be preparedaccording to the procedure outlined in Scheme 7. Cycloaddition of arylcarboximidamide with dialkyl 2-(alkoxymethylene)malonate 24 (R=alkyl)can give the pyrimidinone carboxylate 25 which can be transferred to thecorresponding acid 26 by saponification. Treatment of 26 with achlorinating agent such as POCl₃, PCl₅ or SOCl₂ followed by reactionwith hydrazine can provide the bicyclic derivative 27 which can beconverted to the corresponding halide 28 upon treatment with POX₃ (X=Bror Cl) or SOCl₂. Suzuki coupling of 28 with a boronic acid or esterCyB(OR″)₂ can afford the compound 29.

Alternatively, a series of 1H-pyrazolo[3,4-d]pyrimidine derivatives 29can also be prepared according to the procedure outlined in Scheme 8.Condensation of the known compound, 5-amino-1H-pyrazole-4-carboxamide30, with a suitable aromatic ester (R′=alkyl) can provide the bicyclicpyrazole 31 in the presence of an organic base such as, but not limitedto, NaH, NaOBu-t, NaOEt, KOBu-t in an appropriate solvent such as, butnot limited to, ethanol, isopropyl alcohol, n-butanol. Treatment ofcompound 31 with a chlorinating agent such as POCl₃, PCl₅ or SOCl₂ canafford the corresponding chloride 32 which can be converted to the1H-pyrazolo[3,4-d]pyrimidine derivative 33 by using a reducing agentsuch as Sn or Zn. Compound 33 can be transferred to the desired1H-pyrazolo[3,4-d]pyrimidine derivative 29 by reaction with a suitablehalogenating agent such as NIS, NBS or NCS followed by the Suzukicoupling with a suitable boronic acid or ester as described in Scheme 1.

A series of bicyclic pyrazole derivatives 38 can be prepared by themethods outlined in Scheme 9. Suzuki coupling of 2 with an3,5-dimethoxylphenyl boronic acid or ester can provide the pyrazolederivative 34. Chlorination of compound 34 using sulfuryl chloride cangive the corresponding monochloride 35 (X¹=H, X²=Cl) or dichloride 35(X¹=X²=Cl). Similarly, treatment of compound 34 with Selectfluor® canyield the corresponding monofluoride 35 (X¹=H, X²=F) or difluoride 35(X¹=X²=F). The protecting group of compound 35 can be removed to givethe pyrazole derivative 36. Halogenation of the compound 36 with NIS,NBS or NCS can yield the corresponding pyrazole halide 37 (X=I, Br orCl), which can be further converted to the desired pyrazole derivatives38 by Suzuki coupling with a suitable boronic acid or ester CyB(OR″)₂ asdescribed in Scheme 1.

Alternatively, a series of bicyclic pyrazole derivatives 43 can beprepared by the methods outlined in Scheme 10. Compound 34 can beprepared using procedures as described in the Scheme 9. As describedabove, treatment of compound 34 with Selectfluor® can yield thecorresponding monofluoride 39. Chlorination of the fluoride 39 withsulfuryl chloride, followed by the removal of the protecting group PGcan afford the pyrazole derivatives 41 which can be transferred to thefinal product 43 by halogenation and Suzuki coupling reactions asdescribed in Schemes 1 and 9.

A series of bicyclic pyrazole derivatives 46 can be prepared by themethods outlined in Scheme 11. Cross coupling of a suitable substitutedvinyl derivative 44 (L′ is absent or selected from C₁₋₄ alkylene andC₁₋₄ heteroalkylene; A is selected from Formulas [aa], [bb], and [cc])with pyrazole halide 43 (X=I, Br or Cl; PG=THP, Boc or Cbz etc. . . . )in the presence of a suitable transition metal catalyst and a suitablebase under Heck reaction conditions can afford the corresponding product45. Removal of the protecting group in 45 (PG=THP or Boc or trityl)under acid conditions affords the compound 46.

A series of bicyclic pyrazole derivatives 50 can be prepared by themethods outlined in Scheme 12. Suzuki coupling of 43 with a vinylboronic ester 47 can provide the vinyl pyrazole derivative 48. Heckreaction of 48 with a suitable halide CyX (X=I or Br) under Heckreaction conditions can yield compound 49 which can be transferred tothe pyrazole derivative 50 by removal of the protecting group under theconditions as described previously.

Similarly, a series of alkynylene pyrazole derivatives 53 can beprepared by the methods outlined in Scheme 13. Cross coupling of asuitable substituted ethynyl derivative 51 (L′ is absent or selectedfrom C₁₋₄ alkylene and C₁₋₄ heteroalkylene; A is selected from Formulas[aa], [bb], and [cc]) with pyrazole halide 43 (X=I, Br or Cl; PG=THP,Boc or Cbz etc. . . . ) in the presence of a suitable transition metalcatalyst, CuI and a suitable base under Sonogashira reaction conditionscan afford the corresponding compound 52 which can be transformed to thepyrazole derivative 53 by removal of the protecting group under theconditions as described previously.

A series of ethynylene pyrazole derivatives 56 can be prepared by themethods outlined in Scheme 14. Suzuki coupling of 43 withethynyltrimethylsilane can provide the ethynyl pyrazole derivative 54.Coupling of 54 with a suitable halide CyX (X=I or Br) under Sonogashirareaction conditions can yield compound 55 which can be transferred tothe pyrazole derivative 56 by removal of the protecting group under theconditions as described previously.

Methods of Use

Compounds of the invention can inhibit activity of one or more FGFRenzymes. For example, the compounds of the invention can be used toinhibit activity of an FGFR enzyme in a cell or in an individual orpatient in need of inhibition of the enzyme by administering aninhibiting amount of a compound of the invention to the cell,individual, or patient.

In some embodiments, the compounds of the invention are inhibitors ofone or more of FGFR1, FGFR2, FGFR3, and FGFR4. In some embodiments, thecompounds of the invention inhibit each of FGFR1, FGFR2, and FGFR3. Insome embodiments, the compounds of the invention are selective for oneor more FGFR enzymes. In some embodiments, the compounds of theinvention are selective for one or more FGFR enzymes over VEGFR2. Insome embodiments, the selectivity is 2-fold or more, 3-fold or more,5-fold or more, 10-fold or more, 50-fold or more, or 100-fold or more.

As FGFR inhibitors, the compounds of the invention are useful in thetreatment of various diseases associated with abnormal expression oractivity of FGFR enzymes or FGFR ligands.

For example, the compounds of the invention are useful in the treatmentof cancer. Example cancers include bladder cancer, breast cancer,cervical cancer, colorectal cancer, endometrial cancer, gastric cancer,head and neck cancer, kidney cancer, liver cancer, lung cancer (e.g.,adenocarcinoma, small cell lung cancer and non-small cell lungcarcinomas), ovarian cancer, prostate cancer, esophageal cancer, gallbladder cancer, pancreatic cancer (e.g. exocrine pancreatic carcinoma),stomach cancer, thyroid cancer, skin cancer (e.g., squamous cellcarcinoma).

Further example cancers include hematopoietic malignancies such asleukemia, multiple myeloma, chronic lymphocytic lymphoma, adult T cellleukemia, B-cell lymphoma, acute myelogenous leukemia, Hodgkin's ornon-Hodgkin's lymphoma, myeloproliferative neoplasms (e.g., polycythemiavera, essential thrombocythemia, and primary myelofibrosis),Waldenstrom's Macroglubulinemia, hairy cell lymphoma, and Burkett'slymphoma.

Other cancers treatable with the compounds of the invention includeglioblastoma, melanoma, and rhabdosarcoma.

In addition to oncogenic neoplasms, the compounds of the invention canbe useful in the treatment of skeletal and chondrocyte disordersincluding, but not limited to, achrondroplasia, hypochondroplasia,dwarfism, thanatophoric dysplasia (TD) (clinical forms TD I and TD II),Apert syndrome, Crouzon syndrome, Jackson-Weiss syndrome,Beare-Stevenson cutis gyrate syndrome, Pfeiffer syndrome, andcraniosynostosis syndromes.

The compounds of the invention may further be useful in the treatment offibrotic diseases, such as where a disease symptom or disorder ischaracterized by fibrosis. Example fibrotic diseases include livercirrhosis, glomerulonephritis, pulmonary fibrosis, systemic fibrosis,rheumatoid arthritis, and wound healing.

As used herein, the term “cell” is meant to refer to a cell that is invitro, ex vivo or in vivo. In some embodiments, an ex vivo cell can bepart of a tissue sample excised from an organism such as a mammal. Insome embodiments, an in vitro cell can be a cell in a cell culture. Insome embodiments, an in vivo cell is a cell living in an organism suchas a mammal.

As used herein, the term “contacting” refers to the bringing together ofindicated moieties in an in vitro system or an in vivo system. Forexample, “contacting” the FGFR enzyme with a compound of the inventionincludes the administration of a compound of the present invention to anindividual or patient, such as a human, having FGFR, as well as, forexample, introducing a compound of the invention into a samplecontaining a cellular or purified preparation containing the FGFRenzyme.

As used herein, the term “individual” or “patient,” usedinterchangeably, refers to any animal, including mammals, preferablymice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep,horses, or primates, and most preferably humans.

As used herein, the phrase “therapeutically effective amount” refers tothe amount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue, system, animal, individualor human that is being sought by a researcher, veterinarian, medicaldoctor or other clinician. As used herein the term “treating” or“treatment” refers to 1) preventing the disease; for example, preventinga disease, condition or disorder in an individual who may be predisposedto the disease, condition or disorder but does not yet experience ordisplay the pathology or symptomatology of the disease; 2) inhibitingthe disease; for example, inhibiting a disease, condition or disorder inan individual who is experiencing or displaying the pathology orsymptomatology of the disease, condition or disorder (i.e., arrestingfurther development of the pathology and/or symptomatology), or 3)ameliorating the disease; for example, ameliorating a disease, conditionor disorder in an individual who is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,reversing the pathology and/or symptomatology).

Combination Therapy

One or more additional pharmaceutical agents or treatment methods suchas, for example, anti-viral agents, chemotherapeutics or otheranti-cancer agents, immune enhancers, immunosuppressants, radiation,anti-tumor and anti-viral vaccines, cytokine therapy (e.g., IL2, GM-CSF,etc.), and/or tyrosine kinase inhibitors can be used in combination withthe compounds of the present invention for treatment of FGFR-associateddiseases, disorders or conditions. The agents can be combined with thepresent compounds in a single dosage form, or the agents can beadministered simultaneously or sequentially as separate dosage forms.

Suitable antiviral agents contemplated for use in combination with thecompounds of the present invention can comprise nucleoside andnucleotide reverse transcriptase inhibitors (NRTIs), non-nucleosidereverse transcriptase inhibitors (NNRTIs), protease inhibitors and otherantiviral drugs.

Example suitable NRTIs include zidovudine (AZT); didanosine (ddl);zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir(1592U89); adefovir dipivoxil [bis(POM)-PMEA]; lobucavir (BMS-180194);BCH-10652; emitricitabine [(−)-FTC]; beta-L-FD4 (also called beta-L-D4Cand named beta-L-2′,3′-dicleoxy-5-fluoro-cytidene); DAPD,((−)-beta-D-2,6,-diamino-purine dioxolane); and lodenosine (FddA).Typical suitable NNRTIs include nevirapine (BI-RG-587); delaviradine(BHAP, U-90152); efavirenz (DMP-266); PNU-142721; AG-1549; MKC-442(1-(ethoxy-methyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidinedione);and (+)-calanolide A (NSC-675451) and B. Typical suitable proteaseinhibitors include saquinavir (Ro 31-8959); ritonavir (ABT-538);indinavir (MK-639); nelfnavir (AG-1343); amprenavir (141W94); lasinavir(BMS-234475); DMP-450; BMS-2322623; ABT-378; and AG-1 549. Otherantiviral agents include hydroxyurea, ribavirin, IL-2, IL-12,pentafuside and Yissum Project No. 11607.

Suitable chemotherapeutic or other anti-cancer agents include, forexample, alkylating agents (including, without limitation, nitrogenmustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas andtriazenes) such as uracil mustard, chlormethine, cyclophosphamide(Cytoxan™), ifosfamide, melphalan, chlorambucil, pipobroman,triethylene-melamine, triethylenethiophosphoramine, busulfan,carmustine, lomustine, streptozocin, dacarbazine, and temozolomide.

Other suitable agents for use in combination with the compounds of thepresent invention include: dacarbazine (DTIC), optionally, along withother chemotherapy drugs such as carmustine (BCNU) and cisplatin; the“Dartmouth regimen,” which consists of DTIC, BCNU, cisplatin andtamoxifen; a combination of cisplatin, vinblastine, and DTIC; ortemozolomide. Compounds according to the invention may also be combinedwith immunotherapy drugs, including cytokines such as interferon alpha,interleukin 2, and tumor necrosis factor (TNF) in.

Suitable chemotherapeutic or other anti-cancer agents include, forexample, antimetabolites (including, without limitation, folic acidantagonists, pyrimidine analogs, purine analogs and adenosine deaminaseinhibitors) such as methotrexate, 5-fluorouracil, floxuridine,cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate,pentostatine, and gemcitabine.

Suitable chemotherapeutic or other anti-cancer agents further include,for example, certain natural products and their derivatives (forexample, vinca alkaloids, antitumor antibiotics, enzymes, lymphokinesand epipodophyllotoxins) such as vinblastine, vincristine, vindesine,bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin,idarubicin, ara-C, paclitaxel (TAXOL™), mithramycin, deoxycoformycin,mitomycin-C, L-asparaginase, interferons (especially IFN-a), etoposide,and teniposide.

Other cytotoxic agents include navelbene, CPT-11, anastrazole,letrazole, capecitabine, reloxafine, cyclophosphamide, ifosamide, anddroloxafine.

Also suitable are cytotoxic agents such as epidophyllotoxin; anantineoplastic enzyme; a topoisomerase inhibitor; procarbazine;mitoxantrone; platinum coordination complexes such as cis-platin andcarboplatin; biological response modifiers; growth inhibitors;antihormonal therapeutic agents; leucovorin; tegafur; and haematopoieticgrowth factors.

Other anti-cancer agent(s) include antibody therapeutics such astrastuzumab (Herceptin), antibodies to costimulatory molecules such asCTLA-4, 4-1BB and PD-1, or antibodies to cytokines (IL-10, TGF-β, etc.).

Other anti-cancer agents also include those that block immune cellmigration such as antagonists to chemokine receptors, including CCR2 andCCR4.

Other anti-cancer agents also include those that augment the immunesystem such as adjuvants or adoptive T cell transfer.

Anti-cancer vaccines include dendritic cells, synthetic peptides, DNAvaccines and recombinant viruses.

Methods for the safe and effective administration of most of thesechemotherapeutic agents are known to those skilled in the art. Inaddition, their administration is described in the standard literature.For example, the administration of many of the chemotherapeutic agentsis described in the “Physicians' Desk Reference” (PDR, e.g., 1996edition, Medical Economics Company, Montvale, N.J.), the disclosure ofwhich is incorporated herein by reference as if set forth in itsentirety.

Pharmaceutical Formulations and Dosage Forms

When employed as pharmaceuticals, the compounds of the invention can beadministered in the form of pharmaceutical compositions which refers toa combination of a compound of the invention, or its pharmaceuticallyacceptable salt, and at least one pharmaceutically acceptable carrier.These compositions can be prepared in a manner well known in thepharmaceutical art, and can be administered by a variety of routes,depending upon whether local or systemic treatment is desired and uponthe area to be treated. Administration may be topical (includingophthalmic and to mucous membranes including intranasal, vaginal andrectal delivery), pulmonary (e.g., by inhalation or insufflation ofpowders or aerosols, including by nebulizer; intratracheal, intranasal,epidermal and transdermal), ocular, oral or parenteral. Methods forocular delivery can include topical administration (eye drops),subconjunctival, periocular or intravitreal injection or introduction byballoon catheter or ophthalmic inserts surgically placed in theconjunctival sac. Parenteral administration includes intravenous,intraarterial, subcutaneous, intraperitoneal, or intramuscular injectionor infusion; or intracranial, e.g., intrathecal or intraventricular,administration. Parenteral administration can be in the form of a singlebolus dose, or may be, for example, by a continuous perfusion pump.Pharmaceutical compositions and formulations for topical administrationmay include transdermal patches, ointments, lotions, creams, gels,drops, suppositories, sprays, liquids and powders. Conventionalpharmaceutical carriers, aqueous, powder or oily bases, thickeners andthe like may be necessary or desirable.

This invention also includes pharmaceutical compositions which contain,as the active ingredient, one or more of the compounds of the inventionabove in combination with one or more pharmaceutically acceptablecarriers. In making the compositions of the invention, the activeingredient is typically mixed with an excipient, diluted by an excipientor enclosed within such a carrier in the form of, for example, acapsule, sachet, paper, or other container. When the excipient serves asa diluent, it can be a solid, semi-solid, or liquid material, which actsas a vehicle, carrier or medium for the active ingredient. Thus, thecompositions can be in the form of tablets, pills, powders, lozenges,sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups,aerosols (as a solid or in a liquid medium), ointments containing, forexample, up to 10% by weight of the active compound, soft and hardgelatin capsules, suppositories, sterile injectable solutions, andsterile packaged powders.

In preparing a formulation, the active compound can be milled to providethe appropriate particle size prior to combining with the otheringredients. If the active compound is substantially insoluble, it canbe milled to a particle size of less than 200 mesh. If the activecompound is substantially water soluble, the particle size can beadjusted by milling to provide a substantially uniform distribution inthe formulation, e.g. about 40 mesh.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate, and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

The compositions can be formulated in a unit dosage form, each dosagecontaining from about 5 to about 100 mg, more usually about 10 to about30 mg, of the active ingredient. The term “unit dosage forms” refers tophysically discrete units suitable as unitary dosages for human subjectsand other mammals, each unit containing a predetermined quantity ofactive material calculated to produce the desired therapeutic effect, inassociation with a suitable pharmaceutical excipient.

The active compound can be effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It willbe understood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpre-formulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepre-formulation compositions as homogeneous, the active ingredient istypically dispersed evenly throughout the composition so that thecomposition can be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid pre-formulation isthen subdivided into unit dosage forms of the type described abovecontaining from, for example, 0.1 to about 500 mg of the activeingredient of the present invention.

The tablets or pills of the present invention can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permit theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol, and cellulose acetate.

The liquid forms in which the compounds and compositions of the presentinvention can be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions in can be nebulized by use of inert gases. Nebulizedsolutions may be breathed directly from the nebulizing device or thenebulizing device can be attached to a face masks tent, or intermittentpositive pressure breathing machine. Solution, suspension, or powdercompositions can be administered orally or nasally from devices whichdeliver the formulation in an appropriate manner.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration, and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated aswell as by the judgment of the attending clinician depending uponfactors such as the severity of the disease, the age, weight and generalcondition of the patient, and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers, or stabilizers willresult in the formation of pharmaceutical salts.

The therapeutic dosage of the compounds of the present invention canvary according to, for example, the particular use for which thetreatment is made, the manner of administration of the compound, thehealth and condition of the patient, and the judgment of the prescribingphysician. The proportion or concentration of a compound of theinvention in a pharmaceutical composition can vary depending upon anumber of factors including dosage, chemical characteristics (e.g.,hydrophobicity), and the route of administration. For example, thecompounds of the invention can be provided in an aqueous physiologicalbuffer solution containing about 0.1 to about 10% w/v of the compoundfor parenteral administration. Some typical dose ranges are from about 1μg/kg to about 1 g/kg of body weight per day. In some embodiments, thedose range is from about 0.01 mg/kg to about 100 mg/kg of body weightper day. The dosage is likely to depend on such variables as the typeand extent of progression of the disease or disorder, the overall healthstatus of the particular patient, the relative biological efficacy ofthe compound selected, formulation of the excipient, and its route ofadministration. Effective doses can be extrapolated from dose-responsecurves derived from in vitro or animal model test systems.

The compounds of the invention can also be formulated in combinationwith one or more additional active ingredients which can include anypharmaceutical agent such as anti-viral agents, vaccines, antibodies,immune enhancers, immune suppressants, anti-inflammatory agents and thelike.

Labeled Compounds and Assay Methods

Another aspect of the present invention relates to fluorescent dye, spinlabel, heavy metal or radio-labeled compounds of the invention thatwould be useful not only in imaging but also in assays, both in vitroand in vivo, for localizing and quantitating the FGFR enzyme in tissuesamples, including human, and for identifying FGFR enzyme ligands byinhibition binding of a labeled compound. Accordingly, the presentinvention includes FGFR enzyme assays that contain such labeledcompounds.

The present invention further includes isotopically-labeled compounds ofthe invention. An “isotopically” or “radio-labeled” compound is acompound of the invention where one or more atoms are replaced orsubstituted by an atom having an atomic mass or mass number differentfrom the atomic mass or mass number typically found in nature (i.e.,naturally occurring). Suitable radionuclides that may be incorporated incompounds of the present invention include but are not limited to ²H(also written as D for deuterium), ³H (also written as T for tritium),¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ¹⁸F, ³⁵S, ³⁶Cl, ⁸²Br, ⁷⁵Br,⁷⁶Br, ⁷⁷Br, ¹²³I, ¹²⁴I, ¹²⁵I and ¹³¹I. The radionuclide that isincorporated in the instant radio-labeled compounds will depend on thespecific application of that radio-labeled compound. For example, for invitro FGFR enzyme labeling and competition assays, compounds thatincorporate ³H, ¹⁴C, ⁸²Br, ¹²⁵I, ¹³¹I, or ³⁵S will generally be mostuseful. For radio-imaging applications ¹¹C, ¹⁸F, ¹²⁵I, ¹²³I, ¹²⁴I, ¹³¹I,⁷⁵Br, ⁷⁶Br or ⁷⁷Br will generally be most useful.

It is understood that a “radio-labeled” or “labeled compound” is acompound that has incorporated at least one radionuclide. In someembodiments the radionuclide is selected from the group consisting of³H, ¹⁴C, ¹²⁵I, ³⁵S and ⁸²Br.

Synthetic methods for incorporating radio-isotopes into organiccompounds are applicable to compounds of the invention and are wellknown in the art.

A radio-labeled compound of the invention can be used in a screeningassay to identify/evaluate compounds. In general terms, a newlysynthesized or identified compound (i.e., test compound) can beevaluated for its ability to reduce binding of the radio-labeledcompound of the invention to the FGFR enzyme. Accordingly, the abilityof a test compound to compete with the radio-labeled compound forbinding to the FGFR enzyme directly correlates to its binding affinity.

Kits

The present invention also includes pharmaceutical kits useful, forexample, in the treatment or prevention of FGFR-associated diseases ordisorders, obesity, diabetes and other diseases referred to herein whichinclude one or more containers containing a pharmaceutical compositioncomprising a therapeutically effective amount of a compound of theinvention. Such kits can further include, if desired, one or more ofvarious conventional pharmaceutical kit components, such as, forexample, containers with one or more pharmaceutically acceptablecarriers, additional containers, etc., as will be readily apparent tothose skilled in the art. Instructions, either as inserts or as labels,indicating quantities of the components to be administered, guidelinesfor administration, and/or guidelines for mixing the components, canalso be included in the kit.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of non-criticalparameters which can be changed or modified to yield essentially thesame results. The compounds of the Examples were found to be inhibitorsof one or more FGFR enzymes as described below.

EXAMPLES

Experimental procedures for compounds of the invention are providedbelow. Open Access Prep LC-MS Purifications of some of the compoundsprepared were performed on Waters mass directed fractionation systems.The basic equipment setup, protocols, and control software for theoperation of these systems have been described in detail in theliterature. See e.g. “Two-Pump at Column Dilution Configuration forPreparative LC-MS”, K. Blom, J. Combi. Chem., 4, 295 (2002); “OptimizingPreparative LC-MS Configurations and Methods for Parallel SynthesisPurification”, K. Blom, R. Sparks, J. Doughty, G. Everlof, T. Hague, A.Combs, J. Combi. Chem., 5, 670 (2003); and “Preparative LC-MSPurification: Improved Compound Specific Method Optimization”, K. Blom,B. Glass, R. Sparks, A. Combs, J. Combi. Chem., 6, 874-883 (2004). Thecompounds separated were typically subjected to analytical liquidchromatography mass spectrometry (LCMS) for purity under the followingconditions: Instrument; Agilent 1100 series, LC/MSD, Column: WatersSunfire™ C₁₈ 5 μm, 2.1×5.0 mm, Buffers: mobile phase A: 0.025% TFA inwater and mobile phase B: 0.025% TFA in acetonitrile; gradient 2% to 80%of B in 3 minutes with flow rate 1.5 mL/minute.

Some of the compounds prepared were also separated on a preparativescale by reverse-phase high performance liquid chromatography (RP-HPLC)with MS detector or flash chromatography (silica gel) as indicated inthe Examples. Typical preparative reverse-phase high performance liquidchromatography (RP-HPLC) column conditions are as follows:

pH=2 purifications: Waters Sunfire™ C₁₈ 5 μm, 19×100 mm column, elutingwith mobile phase A: 0.1% TFA (trifluoroacetic acid) in water and mobilephase B: 0.1% TFA in acetonitrile; the flow rate was 30 mL/minute, theseparating gradient was optimized for each compound using the CompoundSpecific Method Optimization protocol as described in the literature[see “Preparative LCMS Purification: Improved Compound Specific MethodOptimization”, K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem.,6, 874-883 (2004)]. Typically, the flow rate used with 30×100 mm columnwas 60 mL/minute;

pH=10 purifications: Waters XBridge C₁₈ 5 μm, 19×100 mm column, elutingwith mobile phase A: 0.15% NH₄OH in water and mobile phase B: 0.15%NH₄OH in acetonitrile; the flow rate was 30 mL/minute, the separatinggradient was optimized for each compound using the Compound SpecificMethod Optimization protocol as described in the literature [See“Preparative LCMS Purification: Improved Compound Specific MethodOptimization”, K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem.,6, 874-883 (2004)]. Typically, the flow rate used with 30×100 mm columnwas 60 mL/minute.

Example 15-[6-(2,6-Dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-N,N-dimethyl-2,3-dihydro-1-benzofuran-2-carboxamide

Step 1: 5-bromo-N,N-dimethyl-2,3-dihydro-1-benzofuran-2-carboxamide

A mixture of 5-bromo-2,3-dihydro-1-benzofuran-2-carboxylic acid (0.243g, 1.00 mmol) (ParkWay, Cat. No. YB-162),benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(0.464 g, 1.05 mmol) and 2.0 M dimethylamine in tetrahydrofuran (THF)(2.00 mL, 4.00 mmol) was stirred at r.t. for 2 h. The volatiles wereremoved under reduced pressure. The residue was purified by flashchromatography on a silica gel column with ethyl acetate in hexanes(gradient: 0-50%) to afford the desired product (0.235 g, 87%). LCMS(M+H)⁺=270.0/272.0.

Step 2:N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1-benzofuran-2-carboxamide

A mixture of 5-bromo-N,N-dimethyl-2,3-dihydro-1-benzofuran-2-carboxamide(0.235 g, 0.870 mmol),4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl] (0.243 g,0.957 mmol) (Aldrich Cat. No. 473294), potassium acetate (0.213 g, 2.17mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)complexed with dichloromethane (1:1) (36 mg, 0.043 mmol); and1,1′-bis(diphenylphosphino)ferrocene (0.024 g, 0.043 mmol) in1,4-dioxane (4.3 mL) was degassed and stirred at 100° C. for 3 h. Aftercooling the mixture was concentrated under reduced pressure. The residuewas purified by flash chromatography on a silica gel column with ethylacetate in hexanes (gradient: 0-50%) to afford the desired product (0.27g, 98%). LCMS (M+H)⁺=318.1.

Step 3:6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine

To a suspension of 6-chloro-1H-pyrazolo[3,4-d]pyrimidine (1.00 g, 6.47mmol) (Ark, Cat. No. AK-30782) in THF (10 mL) at r.t. was addedmethanesulfonic acid (84 μL, 1.3 mmol), followed by dihydropyran (1.77mL, 19.4 mmol). The mixture was stirred at r.t. over weekend. Thereaction mixture was quenched with saturated aqueous NaHCO₃, andextracted with ethyl acetate (3×20 mL). The combined organic layers werewashed with brine, dried over MgSO₄, filtered and concentrated underreduced pressure to afford the crude product which was directly used inthe next step reaction without further purification. LCMS (M-84+H)⁺:m/z=155.1/157.0.

Step 4:6-(3,5-dimethoxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine

A mixture of6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (5.2mmol), (3,5-dimethoxyphenyl)boronic acid (1.0 g, 5.7 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexedwith dichloromethane (1:1) (0.3 g, 0.4 mmol) and potassium phosphate(2.2 g) in 1,4-dioxane (10 mL) and water (2 mL) in a reaction vial wasdegassed and sealed. The mixture was stirred at 100° C. for 3 h. Aftercooling, the reaction mixture was extracted with ethyl acetate (3×20mL). The combined organic layers were washed with brine, dried overMgSO₄, filtered and concentrated under reduced pressure. The residue waspurified by flash chromatography on a silica gel column with ethylacetate in hexanes (0-35%) to afford the desired product. LCMS(M+H)⁺=341.1.

Step 5:6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine

Sulfuryl chloride (0.24 mL, 2.9 mmol) was added to a solution of6-(3,5-dimethoxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine(0.50 g, 1.5 mmol) in acetonitrile (5 mL) at 0° C. under nitrogenatmosphere. The reaction mixture was stirred at r.t. for 30 min, and 2mL of water was added. The mixture was stirred at 40° C. overnight. Thereaction mixture was quenched with saturated aqueous NaHCO₃. Theprecipitates formed were filtered, washed with water then ether, anddried under vacuum to afford the desired product (0.30 g). LCMS(M+H)⁺=325.0/327.0.

Step 6:6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine

N-Iodosuccinimide (0.23 g, 1.0 mmol) was added to a solution of6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine (0.30g) in N,N-dimethylformamide (5.0 mL). The reaction mixture was stirredat 40° C. overnight. The reaction mixture was diluted with water andquenched with aqueous Na₂S₂O₃. The precipitates formed were filtered,washed with water, ether, and dried in vacuum to afford the desiredproduct (0.33 g). LCMS (M+H)⁺=450.8/452.8.

Step 7:5-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-N,N-dimethyl-2,3-dihydro-1-benzofuran-2-carboxamide

A mixture of6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine(18.0 mg, 0.0400 mmol),N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1-benzofuran-2-carboxamide(19.0 mg, 0.0600 mmol), tetrakis(triphenylphosphine)palladium(0) (2.77mg, 0.00240 mmol), and sodium carbonate (12.7 mg, 0.120 mmol) in1,4-dioxane (0.42 mL) and water (0.14 mL) in a reaction vial was sealed,and degassed and recharged with nitrogen for three times. The mixturewas stirred at 120° C. for 3 h. After cooling, the mixture was dilutedwith methanol, and purified by RP-HPLC (pH=10) to afford the desiredproduct. LCMS (M+H)⁺=514.0/516.0. ¹H NMR (300 MHz, DMSO-d₆) δ: 9.77 (s,1H), 8.02 (s, 1H), 7.92 (d, J=8.4 Hz, 1H), 7.06 (s, 1H), 6.97 (d, J=8.4Hz, 1H), 5.76 (d, J=9.1, 7.4 Hz, 1H), 3.99 (s, 6H), 3.55-3.49 (m, 2H),3.13 (s, 3H), 2.90 (s, 3H).

Example 26-[6-(2,6-Dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-N,N-dimethylchromane-2-carboxamide

Step 1:N,N-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chromane-2-carboxamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 1, Steps 1-2 starting with6-bromochromane-2-carboxylic acid (Princeton Bio, Cat. No. PBMR006932).LCMS (M+H)⁺=332.1.

Step 2:6-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-N,N-dimethylchromane-2-carboxamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 1, Step 7 starting from6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidineandN,N-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chromane-2-carboxamide.LCMS (M+H)⁺=528.0/530.0. ¹H NMR (300 MHz, DMSO-d₆) δ: 9.77 (s, 1H), 7.87(s, 1H), 7.85 (d, J=9.1 Hz, 1H), 7.06 (s, 1H), 6.95 (d, J=9.1 Hz, 1H),5.19-5.14 (m, 1H), 3.99 (s, 6H), 3.12 (s, 3H), 2.89 (s, 3H), 2.15-1.95(m, 4H).

Example 35-[6-(2,6-Difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-N,N-dimethyl-2,3-dihydro-1-benzofuran-2-carboxamide

Step 1: 2,4-difluoro-3-iodo-1,5-dimethoxybenzene

To a stirred slurry of 2,6-difluoro-3,5-dimethoxyaniline (6.00 g, 31.7mmol) in 6.0 M hydrogen chloride in water (54 mL, 324 mmol), a solutionof sodium nitrite (2.30 g, 33.3 mmol) in water (12 mL) was addeddrop-wise over 15 min. at 0° C. After an additional 15 min., the resultorange-red slurry was added to a solution of potassium iodide (21.0 g,126 mmol) in water (30 mL) in small-portion at 0° C. The mixture wasthen allowed to stir at r.t. for 1 h. The precipitates were collected byfiltration, washed with water, and dried under reduced pressure. Thefiltrate was neutralized with 6 N NaOH to pH˜7, and extracted with ethylacetate (3×20 mL). The combined organic layers were washed withsaturated Na₂S₂O₃ aqueous solution, dried over MgSO₄, filtered andconcentrated under reduced pressure. The residue combined with theprecipitates collected previously was purified by flash chromatographyon a silica gel column with ethyl acetate in hexanes (gradient: 0-50%)to afford the desired product (6.1 g, 64%). ¹H-NMR (300 MHz, CDCl₃):6.68 (t, J=8.0 Hz, 1H), 3.88 (s, 6H).

Step 2:2-(2,6-difluoro-3,5-dimethoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

To a solution of 2,4-difluoro-3-iodo-1,5-dimethoxybenzene (1.50 g, 5.00mmol) in tetrahedrofuran (THF, 20 mL) was slowly added 2.0 M isopropylmagnesium chloride in THF (2.87 mL, 5.75 mmol) at −10° C. under anatmosphere of nitrogen. After 10 min.,2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.27 mL, 6.25mmol)(Aldrich, Cat. No. 417149) was added. The reaction mixture was thenstirred at ambient temperature for 2 h. The mixture was quenched withsat. NH₄Cl, and extracted with ethyl acetate. The combined organiclayers were washed with water and brine, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue (solid) was treatedwith ethyl ether, filtered, and dried under reduced pressure to affordthe desired product (1.20 g, 80%). ¹H-NMR (400 MHz, CDCl₃): 6.70 (t,J=8.2 Hz, 1H), 3.85 (s, 6H), 1.38 (s, 12H). LCMS (M+H)+=301.1.

Step 3:6-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine

A mixture of6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (477mg, 2.00 mmol),2-(2,6-difluoro-3,5-dimethoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(600. mg, 2.00 mmol), bis(tri-t-butylphosphine)palladium (150.0 mg,0.300 mmol) and diisopropylethylamine (0.700 mL, 4.02 mmol) in1,4-dioxane (20 mL) was degassed and recharged with nitrogen for threetimes. The mixture was stirred at 125° C. overnight. The solvent wasremoved under reduced pressure. The residue was purified by flashchromatography on a silica gel column with ethyl acetate in hexanes(gradient: 0-50%) to afford the desired product (0.30 g, 40%). LCMS(M+H)⁺=377.2.

Step 4:6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine

To a solution of6-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine(0.380 g, 1.01 mmol) in THF (5 mL) and methanol (3 mL) was added HClsolution previously prepared from acetyl chloride (2 mL) in methanol (3mL) at 0° C. The mixture was stirred at r.t. for 2 h. The volatiles wereevaporated under reduced pressure. The residue was diluted with water (5mL), and neutralized with NaOH (2N) to pH˜5. The precipitates (desiredproduct) were collected by filtration and washed with water. Thefiltrate was extracted with ethyl acetate (3×5 mL). The combined organiclayers were dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue (desired product) was combined with theprecipitates collected above to afford the desired product (0.295 g),6-(2,6-difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine, whichwas directly used in the next step reaction without furtherpurification. LCMS (M+H)⁺=293.0.

The above6-(2,6-difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine wasdissolved in DMF (10 mL). To the solution was added N-iodosuccinimide(0.269 g, 1.20 mmol). The mixture was stirred at 50° C. for 24 h. Themixture was diluted with ethyl acetate, washed with aqueous Na₂S₂O₃solution and brine. The organic layer was dried over MgSO₄, filtered andconcentrated under reduced pressure. The residue was purified by flashchromatography on a silica gel column with ethyl acetate in hexanes(gradient: 0-50%) to afford the desired product (0.285 g, 67.5%). LCMS(M+H)⁺=418.9

Step 5:5-[6-(2,6-difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-N,N-dimethyl-2,3-dihydro-1-benzofuran-2-carboxamide

A mixture of6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine(16.7 mg, 0.0400 mmol),N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1-benzofuran-2-carboxamide(19.0 mg, 0.0600 mmol) (Example 1, Step 2),tetrakis(triphenylphosphine)palladium(0) (2.77 mg, 0.00240 mmol) andsodium carbonate (12.7 mg, 0.120 mmol) in 1,4-dioxane (0.42 mL) andwater (0.14 mL) in a reaction vial was sealed, and degassed andrecharged with nitrogen for three times. The mixture was stirred at 115°C. for 5 h. After cooling, the mixture was diluted with methanol, andpurified by RP-HPLC (pH=10) to afford the desired product. LCMS(M+H)⁺=482.0.

Example 45-[6-(2,6-Difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-N,N-dimethyl-2,3-dihydro-1-benzofuran-2-carboxamide(Enantiomer I)

Step 1:N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1-benzofuran-2-carboxamide

The racemicN,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1-benzofuran-2-carboxamide(Example 1, Step 2) was separated by chiral purification using thefollowing conditions: Column: Chiralcel AD-H, 5 μm, 20×250 mm; mobilphase: 20% ethanol in hexanes; gradient: 16 mL/min isoc.; Loading: about25 mg (500 μL) injection); Instrument: Agilent 1100 Preparative HPLC.Two peaks were separated well: peak I: t=9.14 min. peak II: t=14.39 min.LCMS (M+H)⁺=318.1.

Step 2:5-[6-(2,6-Difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-N,N-dimethyl-2,3-dihydro-1-benzofuran-2-carboxamide(Enantiomer I)

A mixture of6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine(15.0 mg, 0.0359 mmol),N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1-benzofuran-2-carboxamide(13.6 mg, 0.0430 mmol) (Peak I),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1) (1.8 mg, 0.0022 mmol) and potassium phosphate(22.8 mg, 0.108 mmol) in 1,4-dioxane (0.48 mL) and water (0.24 mL) in areaction vial was sealed, and degassed and recharged with nitrogen forthree times. The mixture was stirred at 100° C. overnight. Aftercooling, the mixture was diluted with methanol, and purified by RP-HPLC(pH=10) to afford the desired product. LCMS (M+H)⁺=482.1.

Example 55-[6-(2,6-Difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-N,N-dimethyl-2,3-dihydro-1-benzofuran-2-carboxamide(Enantiomer II)

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 4, Step 2 starting from6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidineandN,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1-benzofuran-2-carboxamide(Peak II from chiral separation, Example 4, Step 1). LCMS (M+H)⁺=482.1.¹H NMR (300 MHz, DMSO-d₆) δ: 14.25 (s, 1H), 9.77 (s, 1H), 8.01 (s, 1H),7.91 (d, J=8.5 Hz, 1H), 7.18 (t, J=8.4 Hz, 1H), 6.97 (d, J=8.5 Hz, 1H),5.83-5.70 (m, 1H), 3.94 (s, 6H), 3.55-3.49 (m, 2H), 3.13 (s, 3H), 2.90(s, 3H).

Example 66-[6-(2,6-Difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-N,N-dimethylchromane-2-carboxamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 1, Step 7 starting from6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidineandN,N-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chromane-2-carboxamide.LCMS (M+H)⁺=496.0.

Example 76-(2,6-Difluoro-3,5-dimethoxyphenyl)-3-{2-[(4-methylpiperazin-1-yl)carbonyl]-2,3-dihydro-1-benzofuran-5-yl}-1H-pyrazolo[3,4-d]pyrimidine

Step 1:1[(5-bromo-2,3-dihydro-1-benzofuran-2-yl)carbonyl]-4-methylpiperazine

A mixture of 5-bromo-2,3-dihydro-1-benzofuran-2-carboxylic acid (0.243g, 1.00 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate (0.464 g, 1.05 mmol), 1-methyl-piperazine (116 μL,1.05 mmol) and N,N-diisopropylethylamine (696 μL, 4.00 mmol) was stirredat r.t. for 2 h. The volatiles were removed under reduced pressure. Theresidue was purified by flash chromatography on a silica gel column withethyl acetate in hexanes (gradient: 0-50%) to afford the desired product(0.325 g, 95%). LCMS (M+H)⁺=324.9/327.0.

Step 2:1-methyl-4-{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1-benzofuran-2-yl]carbonyl}piperazine

A mixture of1-[(5-bromo-2,3-dihydro-1-benzofuran-2-yl)carbonyl]-4-methylpiperazine(0.325 g, 1.00 mmol),4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl] (0.279 g,1.10 mmol), potassium acetate (0.245 g, 2.50 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1) (41 mg, 0.050 mmol) and1,1′-bis(diphenylphosphino)ferrocene (28 mg, 0.050 mmol) in 1,4-dioxane(5.0 mL) was degassed and stirred at 105° C. overnight. After coolingthe mixture was concentrated, the residue was purified by flashchromatography on a silica gel column with ethyl acetate in hexanes(gradient: 0-50%) to afford the desired product (0.32 g, 86%). LCMS(M+H-56)⁺=373.2.

Step 3:6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-{2[(4-methylpiperazin-1-yl)carbonyl]-2,3-dihydro-1-benzofuran-5-yl}-1H-pyrazolo[3,4-c]pyrimidine

A mixture of6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine(20.0 mg, 0.0478 mmol),1-methyl-4-{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1-benzofuran-2-yl]carbonyl}piperazine(21.4 mg, 0.0574 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexedwith dichloromethane (1:1) (0.0023 g, 0.0029 mmol), and potassiumphosphate (0.0304 g, 0.143 mmol) in 1,4-dioxane (0.64 mL) and water(0.32 mL) in a reaction vial was sealed, and degassed and recharged withnitrogen for three times. The mixture was stirred at 100° C. overnight.After cooling, the mixture was diluted with methanol, and purified byRP-HPLC (pH=2) to afford the desired product as TFA salt. LCMS(M+H)⁺=537.1.

Example 86-[6-(2,6-Dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-3,4-dihydroisoquinolin-1(2H)-one

Step 1:6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-1(2H)-one

A mixture of 6-bromo-3,4-dihydroisoquinolin-1(2H)-one (904 mg, 4.00mmol), 4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl](559 mg, 2.20 mmol), potassium acetate (491 mg, 5.00 mmol), and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1) (82 mg, 0.10 mmol) in 1,4-dioxane (10 mL) and1,1′-bis(diphenylphosphino)ferrocene (55 mg, 0.10 mmol) was degassed andstirred at 100° C. for 3 h. After cooling it was concentrated. Theresidue was purified by flash chromatography on a silica gel column withethyl acetate in hexanes (gradient: 0-50%) to afford the desired product(1.03 g, 94%). LCMS (M+H)⁺=274.1.

Step 2:6-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-3,4-dihydroisoquinolin-1(2H)-one

A mixture of6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine(18.0 mg, 0.0400 mmol),6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-1(2H)-one(16.4 mg, 0.0600 mmol), tetrakis(triphenylphosphine)palladium(0) (2.77mg, 0.00240 mmol), and sodium carbonate (12.7 mg, 0.120 mmol) in1,4-dioxane (0.42 mL) and water (0.14 mL) in a reaction vial was sealed,and degassed and recharged with nitrogen for three times. The mixturewas stirred at 120° C. for 3 h. After cooling, the mixture was dilutedwith methanol, and purified by RP-HPLC (pH=10) to afford the desiredproduct. LCMS (M+H)⁺=470.0/471.9. ¹H NMR (300 MHz, DMSO-d₆) δ: 9.90 (s,1H), 8.16-7.97 (m, 3H), 7.07 (s, 1H), 4.00 (s, 6H), 3.49-3.40 (m, 2H),3.07 (t, J=6.5 Hz, 3H).

Example 96-[6-(2,6-Dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methyl-3,4-dihydroisoquinolin-1(2H)-one

Step 1:2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-1(2H)-one

Sodium hydride (29.3 mg, 0.732 mmol) was added to a solution of6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-1(2H)-one(100 mg, 0.366 mmol) in DMF (1.0 mL). The mixture was stirred at r.t.for 5 min, and then methyl iodide (57.0 μL, 0.915 mmol) was added. Themixture was stirred at 50° C. for 6 h, then diluted with ethyl acetate,and washed with water and brine. The organic layer was dried over MgSO₄,filtered and concentrated under reduced pressure. The residue waspurified by flash chromatography on a silica gel column with ethylacetate in hexanes (gradient: 0-50%) to afford the desired product(0.038 g, 36%). LCMS (M+H)⁺=274.2.

Step 2:6-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methyl-3,4-dihydroisoquinolin-1(2H)-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 8, Step 2 starting from6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidineand2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-1(2H)-one.LCMS (M+H)⁺=484.1/486.0.

Example 106-[6-(2,6-Dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-ethyl-3,4-dihydroisoquinolin-1(2H)-one

Step 1:2-ethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-1(2H)-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 9, Step 1 starting from6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-1(2H)-oneand iodoethane. LCMS (M+H)⁺=302.1.

Step 2:6-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-ethyl-3,4-dihydroisoquinolin-1(2H)-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 8, Step 2 starting from6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidineand2-ethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-1(2H)-one.LCMS (M+H)⁺=498.1/500.0.

Example 116-[6-(2,6-Dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-isopropyl-3,4-dihydroisoquinolin-1(2H)-one

Step 1:2-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-1(2H)-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 9, Step 1 starting from6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-1(2H)-oneand isopropyl iodide. LCMS (M+H)+=316.1.

Step 2:6-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-isopropyl-3,4-dihydroisoquinolin-1(2H)-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 8, Step 2 starting from6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidineand2-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-1(2H)-one.LCMS (M+H)⁺=511.9/514.0.

Example 126-[6-(2,6-Difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-3,4-dihydroisoquinolin-1(2H)-one

This compound was prepared as a TFA salt by using procedures analogousto those described for the synthesis of Example 7, Step 3 starting from6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidineand6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-1(2H)-one.LCMS (M+H)⁺=438.0.

Example 136-[6-(2,6-Difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline

Step 1: tert-butyl6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 1, Step 2 starting fromtert-butyl 6-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (J&WPharmLab, Cat. No. 50-0272) and4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl]. LCMS(M+H-56)⁺=304.1.

Step 2: tert-butyl6-[6-(2,6-difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-3,4-dihydroisoquinoline-2(1H)-carboxylate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 4, Step 2 starting from6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidineand tert-butyl6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate.LCMS (M+H)⁺=524.1.

Step 3:6-[6-(2,6-difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline

tert-Butyl6-[6-(2,6-difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-3,4-dihydroisoquinoline-2(1H)-carboxylate(10.0 mg, 0.0191 mmol) in methanol (0.10 mL) was treated at r.t. withHCl solution previously prepared from acetyl chloride (0.1 mL) andmethanol (0.1 mL) at 0° C. The mixture was stirred at r.t. for 1 h. Thevolatiles were evaporated. The residue was dissolved in acetonitrile(0.5 mL) and N,N-diisopropylethylamine (30.0 μL, 0.172 mmol). To themixture was added methanesulfonyl chloride (2.0 μL, 0.026 mmol). Themixture was stirred at r.t. for 1 h. The volatiles were removed. Theresidue was dissolved in methanol (0.5 mL) and treated with sodiummethoxide (25%, 0.060 mL). After 1 h, the mixture was diluted withmethanol, and purified by RP-HPLC (pH=10) to afford the desired product.LCMS (M+H)⁺=502.1. ¹H NMR (300 MHz, DMSO-d₆) δ: 9.39 (s, 1H), 7.91 (d,J=7.8 Hz, 1H), 7.89 (s, 1H), 7.25 (d, J=7.8 Hz, 1H), 7.07 (t, J=8.1 Hz,1H), 4.40 (s, 2H), 3.92 (s, 6H), 3.48 (t, J=5.7 Hz, 2H), 3.04 (d, J=5.7Hz, 3H), 2.97 (s, 3H).

Example 146-(2,6-Difluoro-3,5-dimethoxyphenyl)-3-[(4-methoxyphenyl)ethynyl]-1H-pyrazolo[3,4-d]pyrimidine

6-(2,6-Difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine(20.9 mg, 0.0500 mmol) was mixed with 1-ethynyl-4-methoxybenzene (8.26mg, 0.0625 mmol)(Aldrich, cat. No. 206490), copper(I) iodide (0.48 mg,0.0025 mmol), triethylamine (0.010 mL, 0.075 mmol) andbis(triphenylphosphine)palladium(II) chloride (1.8 mg, 0.0025 mmol) inN,N-dimethylformamide (0.10 mL). The reaction mixture was stirred at 60°C. overnight. The mixture was diluted with methanol, and purified byRP-HPLC (pH=2) to afford the desired product as TFA salt. LCMS(M+H)⁺=423.0.

Example 155-[6-(2,6-Difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-(trans-4-hydroxycyclohexyl)isoindolin-1-one

Step 1: 5-bromo-2-(trans-4-hydroxycyclohexyl)isoindolin-1-one

A mixture of methyl 4-bromo-2-(bromomethyl)benzoate (0.500 g, 1.62mmol), trans-4-aminocyclohexanol hydrochloride (0.295 g, 1.95 mmol), andpotassium carbonate (0.44 g, 3.2 mmol) in ethanol (5.0 mL) was stirredin a sealed vial at 50° C. for 4 h. After cooling, the mixture wasdiluted with ethyl acetate (10 mL), and was filtered. The filtrate wasconcentrated under reduced pressure. The residue was triturated withethyl ether (3 mL). The precipitates were collected by filtration andwashed with ethyl ether to afford the desired product. LCMS(M+H)⁺=309.9/312.0.

Step 2:2-(trans-4-hydroxycyclohexyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 1, Step 2 starting from5-bromo-2-(trans-4-hydroxycyclohexyl)isoindolin-1-one and4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl]. LCMS(M+H)⁺=358.1.

Step 3:5-[6-(2,6-difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-(trans-4-hydroxycyclohexyl)isoindolin-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 4, Step 2 starting from6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidineand2-(trans-4-hydroxycyclohexyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one.LCMS (M+H)⁺=522.0.

Example 165-[6-(2,6-Difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-(cis-4-hydroxycyclohexyl)isoindolin-1-one

Step 1: 5-bromo-2-(cis-4-hydroxycyclohexyl)isoindolin-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 15, Step 1 starting from methyl4-bromo-2-(bromomethyl)benzoate and cis-4-aminocyclohexanolhydrochloride. LCMS (M+H)⁺=310.0/312.0.

Step 2:2-(cis-4-hydroxycyclohexyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 1, Step 2 starting from5-bromo-2-(cis-4-hydroxycyclohexyl)isoindolin-1-one and4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl]. LCMS(M+H)⁺=358.1.

Step 3:5-[6-(2,6-difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-(cis-4-hydroxycyclohexyl)isoindolin-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 4, Step 2 starting from6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidineand2-(cis-4-hydroxycyclohexyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one.LCMS (M+H)⁺=522.1.

Example 176-(2,6-Difluoro-3,5-dimethoxyphenyl)-3-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrazolo[3,4-d]pyrimidine

This compound was prepared as a TFA salt by using procedures analogousto those described for the synthesis of Example 7, Step 3 starting from6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidineand1-methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine.LCMS (M+H)⁺=467.0.

Example 186-(2,6-Difluoro-3,5-dimethoxyphenyl)-3-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-1H-pyrazolo[3,4-d]pyrimidine

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 4, Step 2 starting from6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidineand1-methyl-4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]piperazine.LCMS (M+H)⁺=468.0.

Example 196-(2,6-Difluoro-3,5-dimethoxyphenyl)-3-[2-(4-methylpiperazin-1-yl)pyridin-4-yl]-1H-pyrazolo[3,4-d]pyrimidine

This compound was prepared as TFA salt by using procedures analogous tothose described for the synthesis of Example 7, Step 3 starting from6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidineand1-methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]piperazine.LCMS (M+H)⁺=468.1.

Example 202-{4-[6-(2,6-Difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]phenoxy}-N,N-dimethylethanamine

This compound was prepared as TFA salt by using procedures analogous tothose described for the synthesis of Example 7, Step 3 starting from6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidineandN,N-dimethyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethanamine(Combi-Blocks, Cat. No. PN-3972). LCMS (M+H)⁺=456.1.

Example 212-Cyclopropyl-5-[6-(2,6-difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]isoindolin-1-one

Step 1: 5-bromo-2-cyclopropylisoindolin-1-one

A mixture of methyl 4-bromo-2-(bromomethyl)benzoate (Ark Pharm, Cat. No.AK-26333) (0.5 g, 0.002 mol), cyclopropylamine (0.17 mL, 0.0024 mol) andpotassium carbonate (0.45 g, 0.0032 mol) in ethanol (5 mL) was stirredat 40° C. for 3 h. The reaction mixture was quenched with water andextracted with ethyl acetate. The organic layers were washed with brine,dried with Na₂SO₄, filtered, and concentrated under reduced pressure togive a crude product which was directly used in nest step reactionwithout further purification. LCMS (M+H)⁺=252.0/254.0.

Step 2:2-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one

To a solution of 5-bromo-2-cyclopropylisoindolin-1-one (0.51 g, 0.0020mol) and 4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl](0.56 g, 0.0022 mol) in 1,4-dioxane (5 mL) was added[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1) (0.08 g, 0.0001 mol), potassium acetate (0.60 g,0.0061 mol), and 1,1′-bis(diphenylphosphino)ferrocene (0.06 g, 0.0001mol) under an atmosphere of nitrogen. The reaction mixture was stirredat 80° C. overnight. After cooled to r.t., the mixture was filteredthrough a pad of Celite, washed with ethyl acetate, and concentrated.The residue was purified by flash chromatography on a silica gel columnwith ethyl acetate in hexanes (0-40%) to afford the desired product.LCMS (M+H)⁺=300.1.

Step 3:2-cyclopropyl-5-[6-(2,6-difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]isoindolin-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 4, Step 2 starting from6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidineand2-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one.LCMS (M+H)⁺=464.1. ¹H NMR (300 MHz, DMSO-d₆) δ: 9.86 (s, 1H), 8.34 (s,1H), 8.27 (d, J=8.0 Hz, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.18 (t, J=8.3 Hz,1H), 4.52 (s, 2H), 3.94 (s, 6H), 3.07-2.90 (m, 1H), 0.97-0.76 (m, 4H).

Example 225-[6-(2,6-Dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-(cis-4-hydroxycyclohexyl)isoindolin-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 1, Step 7 starting from6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidineand2-(cis-4-hydroxycyclohexyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one.LCMS (M+H)⁺=553.9/555.9. ¹H NMR (300 MHz, DMSO-d₆) δ: 9.90 (s, 1H), 8.40(s, 1H), 8.28 (d, J=7.9 Hz, 1H), 7.83 (d, J=7.9 Hz, 1H), 7.08 (s, 1H),4.57 (s, 2H), 4.48 (d, J=3.1 Hz, 1H), 4.13-4.01 (m, 1H), 4.00 (s, 6H),3.91-3.85 (m, 1H), 2.03-1.91 (m, 2H), 1.85-1.73 (m, 2H), 1.67-1.42 (m,4H).

Example 235-[6-(2,6-Dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-(trans-4-hydroxycyclohexyl)isoindolin-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 1, Step 7 starting from6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidineand2-(trans-4-hydroxycyclohexyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one.LCMS (M+H)⁺=554.1/556.0.

Example 246-(2,6-Difluoro-3,5-dimethoxyphenyl)-3-{2-[(4-methylpiperazin-1-yl)carbonyl]-2,3-dihydro-1-benzofuran-5-yl}-1H-pyrazolo[4,3-c]pyridine

Step 1: 6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine

At r.t. to a suspension of 6-chloro-1H-pyrazolo[4,3-c]pyridine (0.5 g, 3mmol) (Frontier Cat. No. Z13659) in methylene chloride (3 mL) and THF (1mL) was added methanesulfonic acid (42 μL, 0.65 mmol), followed bydihydropyran (0.89 mL, 9.8 mmol). The mixture was stirred at r.t. for 2h., and then at 50° C. overnight. After cooling the mixture wasconcentrated under reduced pressure. The residue was purified by flashchromatography on a silica gel column with ethyl acetate in hexanes(0-50%) to afford the desired product (0.8 g). LCMS (M+H)⁺=238.0; LCMS(M-84+H)⁺=154.0/156.0.

Step 2:6-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine

A mixture of6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine (333mg, 1.40 mmol),2-(2,6-difluoro-3,5-dimethoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(400.0 mg, 1.333 mmol),dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (21.0 mg, 0.0266 mmol), and potassium phosphate (566 mg, 2.66mmol) in tetrahydrofuran (3 mL) and water (5.5 mL) in a reaction vialwas degassed and sealed. The mixture was stirred at r.t. for 30 min. Themixture was extracted with ethyl acetate. The organic layer was driedover MgSO₄, filtered and concentrated under reduced pressure. Theresidue was purified by flash chromatography on a silica gel column withethyl acetate in hexanes (gradient: 0-50%) to afford the desired product(0.38 g, 76%). LCMS (M+H)⁺=376.1.

Step 3:6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[4,3-c]pyridine

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 1, Step 5-6 starting from6-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridineand N-iodosuccinimide. LCMS (M+H)⁺=418.0.

Step 4:6-(2,6-Difluoro-3,5-dimethoxyphenyl)-3-{2-[(4-methylpiperazin-1-yl)carbonyl]-2,3-dihydro-1-benzofuran-5-yl}-1H-pyrazolo[4,3-c]pyridine

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 4, Step 2 starting from6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[4,3-c]pyridineand1-methyl-4-{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1-benzofuran-2-yl]carbonyl}piperazine.LCMS (M+H)⁺=536.2.

Example 256-(2,6-Difluoro-3,5-dimethoxyphenyl)-3-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrazolo[4,3-c]pyridine

This compound was prepared as TFA salt by using procedures analogous tothose described for the synthesis of Example 7, Step 3 starting from6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[4,3-c]pyridineand1-methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine.LCMS (M+H)⁺=466.2.

Example 266-(2,6-Difluoro-3,5-dimethoxyphenyl)-3-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-1H-pyrazolo[4,3-c]pyridine

This compound was prepared as TFA salt by using procedures analogous tothose described for the synthesis of Example 7, Step 3 starting from6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[4,3-c]pyridineand1-methyl-4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]piperazine.LCMS (M+H)⁺=467.2.

Example 276-(2,6-Difluoro-3,5-dimethoxyphenyl)-3-[2-(4-methylpiperazin-1-yl)pyridin-4-yl]-1H-pyrazolo[4,3-c]pyridine

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 4, Step 2 starting from6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[4,3-c]pyridineand1-methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]piperazine.LCMS (M+H)⁺=467.2.

Example 282-Cyclopropyl-5-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]isoindolin-1-one

Step 1:6-(3,5-dimethoxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine

A mixture of6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine (0.80g, 3.4 mmol) (Example 24, Step 1),2-(3,5-dimethoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.1 g,4.0 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)complexed with dichloromethane (1:1) (200 mg, 0.3 mmol), and potassiumphosphate (1400 mg, 6.7 mmol) in 1,4-dioxane (7 mL) and water (1 mL) ina reaction vial was degassed and sealed. It was stirred at 90° C. for 2h. After cooling it was concentrated under reduced pressure. The residuewas purified by flash chromatography on a silica gel column with ethylacetate in hexanes (0-50%) to afford the desired product (660 mg). LCMS(M+H)⁺=340.1.

Step 2:6-(2,6-dichloro-3,5-dimethoxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine

At r.t. to a solution of6-(3,5-dimethoxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine(0.66 g, 1.9 mmol) in methylene chloride (10 mL) with stirring was addeddrop-wise sulfuryl chloride (300 μL, 3.7 mmol)(Acros Organics, Cat. No.37815). The mixture was stirred at r.t. for 2 h. LCMS showed 25% productformed, and 75% was mono-chlorinated product. Additional sulfurylchloride (100 μL) was added to the mixture. It was stirred at r.t. for 5h, and then concentrated under reduced pressure. The residue waspurified by flash chromatography on a silica gel column with ethylacetate in hexanes (0-50%) to afford the desired product (0.78 g). LCMS(M+H)⁺=408.0.

Step 3: 6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridine

At 0° C. (with ice-bath) to a stirring solution of6-(2,6-dichloro-3,5-dimethoxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine(0.78 g, 1.9 mmol) in methanol (10 mL) was added drop-wise a pre-cooled(with ice-bath) HCl solution prepared from acetyl chloride (2.72 mL,38.2 mmol) in methanol (15 mL). After the addition, the ice-bath wasremoved. The mixture was stirred at r.t. for 2 h, and then concentratedunder reduced pressure. The residue was purified by flash chromatographyon a silica gel column with ethyl acetate in hexanes (0-50%) to affordthe desired product (0.62 g). LC/MS (M+H)⁺=324.0.

Step 4:6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[4,3-c]pyridine

At r.t. to a stirring solution of6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridine (0.62 g,1.9 mmol) in methylene chloride (10 mL) was added N-iodosuccinimide(0.47 g, 2.1 mmol). The mixture was stirred at r.t. for 2 h. It wasconcentrated under reduced pressure. The residue was purified by flashchromatography on a silica gel column with ethyl acetate in hexanes(0-50%) to afford the desired product 0.50 g.

Step 5:2-Cyclopropyl-5-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]isoindolin-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 4, Step 2 starting from6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[4,3-c]pyridineand2-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one(Example 21, Step 2). LCMS (M+H)⁺=495.1/497.1.

Example 292-{4-[6-(2,6-Dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-2-methylphenoxy}-N,N-dimethylacetamide

Step 1: 2-(4-bromo-2-methylphenoxy)-N,N-dimethylacetamide

The reaction mixture of 4-bromo-2-methylphenol (Aldrich, Cat. No.681121) (0.50 g, 2.7 mmol), 2-chloro-N,N-dimethylacetamide (Aldrich,Cat. No. 24350) (0.27 mL, 2.7 mmol) and potassium carbonate (1.1 g, 8.0mmol) in DMF (4 mL) was stirred at 60° C. overnight. After cooling tor.t., the mixture was adjusted to pH˜2 with aqueous HCl, and extractedwith ethyl acetate (3×20 mL). The combined organic layers were driedover MgSO₄, filtered, and concentrated under reduced pressure to affordthe product which was directly used in nest step reaction withoutfurther purification. LCMS (M+H)⁺=272.2/274.2.

Step 2:N,N-dimethyl-2-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]acetamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 1, Step 2 starting from2-(4-bromo-2-methylphenoxy)-N,N-dimethylacetamide and4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl]. LCMS(M+H)⁺=320.4.

Step 3:2-{4-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-2-methylphenoxy}-N,N-dimethylacetamide

This compound was prepared using procedures analogous to those describedfor the synthesis of Example 4, Step 2 starting from6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[4,3-c]pyridineandN,N-dimethyl-2-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]acetamide.LCMS (M+H)⁺=515.1/517.1.

Example 306-[6-(2,6-Dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-2H-1,4-benzoxazin-3(4H)-one

Step 1:6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,4-benzoxazin-3(4H)-one

This compound was prepared using procedures analogous to those describedin Example 1, Step 2 starting from 6-bromo-2H-1,4-benzoxazin-3(4H)-one(Aldrich, Cat. No. 662348) and4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl]. LCMS(M+H)⁺=276.3.

Step 2:6-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-2H-1,4-benzoxazin-3(4H)-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 4, Step 2 starting from6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[4,3-c]pyridineand6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,4-benzoxazin-3(4H)-one.LCMS (M+H)⁺=471.0/473.0.

Example 316-[6-(2,6-Dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-4-methyl-2H-1,4-benzoxazin-3(4H)-one

Step 1: 6-bromo-4-methyl-2H-1,4-benzoxazin-3(4H)-one

Sodium hydride (0.10 g, 2.6 mmol) was added to a solution of6-bromo-2H-1,4-benzoxazin-3(4H)-one (0.49 g, 2.1 mmol) inN,N-dimethylformamide (3 mL) under nitrogen. After the mixture wasstirred at r.t. for 10 min, methyl iodide (0.27 mL, 4.3 mmol) was added.The reaction mixture was stirred at r.t. for 1 h. Then 10 mL of waterwas added to the mixture, and a white precipitate was removed byfiltration, washed with water, and dried under vacuum to afford theproduct which was directly used in next step reaction without furtherpurification. LCMS (M+H)⁺=242.2/244.2.

Step 2:4-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,4-benzoxazin-3(4H)-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 1, Step 2 starting from6-bromo-4-methyl-2H-1,4-benzoxazin-3(4H)-one and4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl]. LCMS(M+H)⁺=290.3.

Step 3:6-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-4-methyl-2H-1,4-benzoxazin-3(4H)-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 4, Step 2 starting from6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[4,3-c]pyridineand4-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,4-benzoxazin-3(4H)-one.LCMS (M+H)⁺=485.0/487.0.

Example 325-[6-(2,6-Dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-2-benzofuran-1(3H)-one

Step 1:5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-benzofuran-1(3H)-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 1, Step 2 starting from5-bromo-2-benzofuran-1(3H)-one (Aldrich, Cat. No. 647187) and4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl].

Step 2:5-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-y]-2-benzofuran-1(3H)-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 4, Step 2 starting from6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[4,3-c]pyridineand5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-benzofuran-1(3H)-one.LCMS (M+H)⁺: 456.0/458.0.

Example 332-{4-[6-(2,6-Dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-1H-pyrazol-1-yl}propanenitrile

Step 1:2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propanenitrile

A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(Aldrich, Cat. No. 525057)(0.22 g, 1.1 mmol), 2-chloropropanenitrile(Aldrich, Cat. No. 192406) (0.12 g, 1.4 mmol), and cesium carbonate(0.82 g, 2.5 mmol) in acetonitrile (4.0 mL) was stirred at 80° C. for 2h. The reaction mixture was diluted with water, extracted with ethylacetate, washed with brine. The combined organic layers were dried overMgSO₄, filtered and concentrated under reduced pressure. The residue waspurified by flash chromatography on a silica gel column with ethylacetate in hexanes (0-40%) to afford the desired product. LCMS(M+H)⁺=248.1.

Step 2:2-{4-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-1H-pyrazol-1-yl}propanenitrile

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 4, Step 2 starting from6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[4,3-c]pyridineand2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propanenitrile.LCMS (M+H)⁺=443.0/445.0. ¹H NMR (300 MHz, DMSO-d₆) δ: 9.39 (s, 1H), 8.66(s, 1H), 8.27 (s, 1H), 7.42 (s, 1H), 7.00 (s, 1H), 5.91 (q, J=7.1 Hz,1H), 3.96 (s, 6H), 1.88 (d, J=7.1 Hz, 3H).

Example 342-{4-[6-(2,6-Dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-2-fluorophenyl}-2-hydroxy-N,N-dimethylacetamide

Step 1: 2-(4-bromo-2-fluorophenyl)-2-hydroxy-N,N-dimethylacetamide

N,N-Diisopropylethylamine (0.8 g, 0.006 mol) was added to a mixture of(4-bromo-2-fluorophenyl)(hydroxy)acetic acid (Oakwood, Cat. No. 019267)(0.5 g, 0.002 mol), dimethylamine in THF (2.4 mmol, 2.0 M, 1.2 mL), andbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(1.1 g, 0.0024 mol) in methylene chloride (10 mL). The mixture wasstirred at r.t. overnight, and concentrated under reduced pressure. Theresidue was purified by flash chromatography on a silica gel column withethyl acetate in hexanes (0-40%) to afford the desired product. LCMS(M+H)⁺=276.2/278.2. ¹H NMR (300 MHz, DMSO-d₆) δ: 9.50 (d, J=1.1 Hz, 1H),7.97 (dd, J=8.0, 1.5 Hz, 1H), 7.83 (dd, J=11.4, 1.5 Hz, 1H), 7.54 (d,J=8.0 Hz, 1H), 7.51 (d, J=1.1 Hz, 1H), 7.01 (s, 1H), 5.70 (s, 1H), 5.65(s, 1H), 3.96 (s, 6H), 2.94 (s, 3H), 2.88 (s, 3H).

Step 2:2-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-hydroxy-N,N-dimethylacetamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 1, Step 2 starting from2-(4-bromo-2-fluorophenyl)-2-hydroxy-N,N-dimethylacetamide and4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl]. LCMS(M+H)⁺=324.2.

Step 3:2-{4-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-2-fluorophenyl}-2-hydroxy-N,N-dimethylacetamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 4, Step 2 starting from6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[4,3-c]pyridineand {4-[2-(dimethylamino)-1-hydroxy-2-oxoethyl]-3-fluorophenyl}boronicacid. LCMS (M+H)⁺=519.0/521.0.

Example 352-{4-[6-(2,6-Dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]phenoxy}-N,N-dimethylethanamine

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 4, Step 2 starting from6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[4,3-c]pyridineandN,N-dimethyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethanamine(Combi-Blocks, Cat. No. PN-3972). LCMS (M+H)⁺=487.0/489.0.

Example 362-{4-[6-(2,6-Dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-1H-pyrazol-1-yl}-N-methylacetamide

Step 1:{4-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-1H-pyrazol-1-yl}aceticacid

A mixture of6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[4,3-c]pyridine(0.20 g, 0.44 mmol),ethyl[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]acetate(Aldrich, Cat. No. 683566) (0.14 g, 0.49 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexedwith dichloromethane (1:1) (18 mg, 0.022 mmol), and potassium carbonate(0.184 g, 1.33 mmol) in 1,4-dioxane (10 mL) and water (5 mL) wasdegassed and recharged with nitrogen three times. The reaction mixturewas stirred at 85° C. for 6 h. The reaction mixture was adjusted to pH˜4with 1N HCl. The precipitates formed were filtered, washed with waterand ether, and dried under vacuum to afford the desired product (0.10 g,50%). LCMS (M+H)⁺=448.0/450.0.

Step 2:2-{4-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-1H-pyrazol-1-yl}-N-methylacetamide

N,N-Diisopropylethylamine (9.3 μL, 0.054 mmol) was added to a mixture of{4-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-1H-pyrazol-1-yl}aceticacid (8.0 mg, 0.018 mmol), 2.0 M methylamine in THF (9.8 μL, 0.020 mmol)and benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate (8.7 mg, 0.020 mmol) in N,N-dimethylformamide (0.5mL). The reaction mixture was stirred at r.t. for 3 h, and purified byRP-HPLC (pH=10) to afford the desired product. LCMS (M+H)⁺=461.0/463.0.

Example 372-{4-[6-(2,6-Dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-1H-pyrazol-1-yl}-N,N-dimethylacetamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 36, Step 2, starting from{4-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-1H-pyrazol-1-yl}aceticacid and 2.0 M dimethylamine in THF. LCMS (M+H)⁺=475.0/477.0.

Example 38N-Cyclopropyl-2-{4-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-1H-pyrazol-1-yl}acetamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 36, Step 2, starting from{4-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-1H-pyrazol-1-yl}aceticacid and cyclopropylamine. LCMS (M+H)⁺=487.1/489.1.

Example 391-({4-[6-(2,6-Dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-1H-pyrazol-1-yl}acetyl)azetidin-3-ol

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 36, Step 2, starting from{4-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-1H-pyrazol-1-yl}aceticacid and azetidin-3-ol hydrochloride (Aldrich, Cat. No. 680079). LCMS(M+H)⁺=503.1/505.3.

Example 406-(2,6-Dichloro-3,5-dimethoxyphenyl)-3-[1-(2-morpholin-4-yl-2-oxoethyl)-1H-pyrazol-4-yl]-1H-pyrazolo[4,3-c]pyridine

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 36, Step 2, starting from{4-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-1H-pyrazol-1-yl}aceticacid and morpholine. LCMS (M+H)⁺=517.0/519.0.

Example 416-(2,6-Dichloro-3,5-dimethoxyphenyl)-3-{1-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-1H-pyrazol-4-yl}-1H-pyrazolo[4,3-c]pyridine

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 36, Step 2, starting from{4-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-1H-pyrazol-1-yl}aceticacid and 1-methyl piperazine. LCMS (M+H)⁺=530.1/532.1.

Example 422-{4-[6-(2,6-Dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-1H-pyrazol-1-yl}-N-(1-methylpiperidin-4-yl)acetamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 36, Step 2, starting from{4-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-1H-pyrazol-1-yl}aceticacid and 1-methylpiperidin-4-amine. LCMS (M+H)⁺=544.1/546.1.

Example 431-({4-[6-(2,6-Dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-1H-pyrazol-1-yl}acetyl)pyrrolidin-3-ol

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 36, Step 2, starting from{4-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-1H-pyrazol-1-yl}aceticacid and 3-pyrrolidinol. LCMS (M+H)⁺=517.1/519.0.

Example 441-({4-[6-(2,6-Dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-1H-pyrazol-1-yl}acetyl)-N,N-dimethylpyrrolidin-3-amine

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 36, Step 2, starting from{4-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-1H-pyrazol-1-yl}aceticacid and N,N-dimethylpyrrolidin-3-amine. LCMS (M+H)⁺=544.2/546.3.

Example 456-(2,6-Dichloro-3,5-dimethoxyphenyl)-3-{1-[2-(3-methoxypyrrolidin-1-yl)-2-oxoethyl]-1H-pyrazol-4-yl}-1H-pyrazolo[4,3-c]pyridine

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 36, Step 2, starting from{4-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-1H-pyrazol-1-yl}aceticacid and 3-methoxypyrrolidine. LCMS (M+H)⁺=531.2/533.2.

Example 462-{4-[6-(2,6-Dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-1H-pyrazol-1-yl}-N-(2-methoxyethyl)acetamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 36, Step 2, starting from{4-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-1H-pyrazol-1-yl}aceticacid and 2-Methoxyethylamine. LCMS (M+H)⁺=505.1/507.1.

Example 471-({4-[6-(2,6-Dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-1H-pyrazol-1-yl}acetyl)pyrrolidine-3-carbonitrile

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 36, Step 2, starting from{4-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-1H-pyrazol-1-yl}aceticacid and pyrrolidine-3-carbonitrile hydrochloride. LCMS(M+H)⁺=526.2/528.1.

Example 486-(2,6-Dichloro-3,5-dimethoxyphenyl)-3-(1-{2-[(3S)-3-fluoropyrrolidin-1-yl]-2-oxoethyl}-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 36, Step 2, starting from{4-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-1H-pyrazol-1-yl}aceticacid and (3S)-3-fluoropyrrolidine hydrochloride. LCMS(M+H)⁺=519.1/521.1.

Example 496-(2,6-Dichloro-3,5-dimethoxyphenyl)-3-[(E)-2-(1-methyl-1H-pyrazol-4-yl)vinyl]-1H-pyrazolo[4,3-c]pyridine

Step 1:6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine

A mixture of6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[4,3-c]pyridine(0.45 g, 1.0 mmol) (Example 28, Step 4), dihydropyran (270 μL, 3.0 mmol)and methanesulfonic acid (13 μL, 0.20 mmol) in methylene chloride (9 mL)and tetrahydrofuran (3 mL) in reaction flask was stirred at r.t.overnight. The mixture was concentrated under reduced pressure. Theresidue was purified by flash chromatography on a silica gel column withethyl acetate in hexanes (0-50%) to afford the desired product (0.34 g,64%). LC/MS (M+H)⁺=534.0.

Step 2:6-(2,6-dichloro-3,5-dimethoxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-pyrazolo[4,3-c]pyridine

A mixture of6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine(100 mg, 0.2 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (44μL, 0.26 mmol) (Aldrich Cat. No. 633348), tributylamine (54 μL, 0.22mmol) and dichloro[bis(triphenylphosphoranyl)]palladium (5 mg, 0.007mmol) in N,N-dimethylformamide (1 mL) in a reaction vial was degassedand sealed. The mixture was stirred at 95° C. for 15 h. After cooling itwas equally split into two parts. The material was used in the next stepwithout further purification.

Step 3:6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-[(E)-2-(1-methyl-1H-pyrazol-4-yl)vinyl]-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine

To a solution of6-(2,6-dichloro-3,5-dimethoxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-pyrazolo[4,3-c]pyridine(0.1 mmol) in N,N-dimethylformamide (0.5 mL) was added4-iodo-1-methyl-1H-pyrazole (22 mg, 0.10 mmol) (Aldrich Cat. No.683531), barium hydroxide (36 mg, 0.21 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexedwith dichloromethane (1:1) (5.6 mg, 0.0069 mmol), and water (0.05 mL).The mixture was degassed and sealed. The mixture was stirred at 95° C.overnight. After cooling the solid was filtered off, washed withacetonitrile. The filtrate was concentrated under reduced pressure toafford the crude product which was directly used in next step reactionwithout further purification. LCMS (M+H)⁺=514.2/516.1.

Step 4:6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-[(E)-2-(1-methyl-1H-pyrazol-4-yl)vinyl]-1H-pyrazolo[4,3-c]pyridine

6-(2,6-Dichloro-3,5-dimethoxyphenyl)-3-[(E)-2-(1-methyl-1H-pyrazol-4-yl)vinyl]-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridinewas dissolved in methanol (0.8 mL). To the solution was added HClsolution previously prepared from acetyl chloride (0.5 mL) and methanol(0.5 mL). The mixture was stirred at r.t. for 2 h. The solvent wasremoved. The residue was dissolved in methanol, and purified by RP-HPLC(pH=10) to afford the desired product (4.9 mg). LCMS (M+H)⁺=430.1.

Example 502-(4-{(E)-2-[6-(2,6-Dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]vinyl}-1H-pyrazol-1-yl)ethanol

Step 1: 4-iodo-1-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1H-pyrazole

At r.t. to a solution of 2-(2-bromoethoxy)tetrahydro-2H-pyran (210 μL,1.4 mmol) (Aldrich Cat. No. 475394) in acetonitrile (6 mL) was added4-iodo-1H-pyrazole (0.25 g, 1.3 mmol) (Aldrich Cat. No. 213993),followed by cesium carbonate (0.63 g, 1.9 mmol). The mixture was stirredat r.t. over a weekend. The solid was filtered off, then washed withacetonitrile. The filtrate was concentrated under reduced pressure. Theresidue was purified by flash chromatography on a silica gel column withethyl acetate in hexanes (0-50%) to afford the desired product (0.12 g).LCMS (M-84)⁺=239.0.

Step 2:6-(2,6-dichloro-3,5-dimethoxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-3-((E)-2-{1-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1H-pyrazol-4-yl}vinyl)-1H-pyrazolo[4,3-c]pyridine

To a solution of6-(2,6-dichloro-3,5-dimethoxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-pyrazolo[4,3-c]pyridine(0.1 mmol) in DMF (0.5 mL) was added4-iodo-1-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1H-pyrazole (44 mg, 0.14mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)complexed with dichloromethane (1:1) (7.5 mg, 0.0092 mmol), and water(0.05 mL). The mixture was degassed and sealed. It was stirred at 95° C.for 3 h. After cooling the solid was filtered off, washed withacetonitrile. The filtrate was concentrated under reduced pressure. Theresidue was purified by flash chromatography on a silica gel column withethyl acetate in hexanes (0-50%) to afford the desired product (32 mg).LCMS (M+H)⁺=628.2/630.3.

Step 3:2-(4-{(E)-2-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]vinyl}-1H-pyrazol-1-yl)ethanol

6-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-3-((E)-2-{1-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1H-pyrazol-4-yl}vinyl)-1H-pyrazolo[4,3-c]pyridine(32 mg) was dissolved in methanol (1 mL). To the solution was added HClsolution previously prepared from acetyl chloride (0.5 mL) and methanol(0.5 mL). The mixture was stirred at r.t. for 30 min. The solvent wasremoved. The residue was dissolved in methanol, purified by RP-HPLC(pH=2) to afford the desired product as TFA salt. LCMS (M+H)⁺=460.0.

Example 51(2S)-1-{4-[6-(2,6-Dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-1H-pyrazol-1-yl}propan-2-ol

Step 1:(2S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propan-2-ol

A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(300 mg, 1.5 mmol)(Aldrich Cat. No. 525057), (S)-(−)-methyloxirane (130μL, 1.9 mmol) and triethylamine (0.45 mL, 3.2 mmol) in acetonitrile (1.0mL) in a reaction vial was stirred at 50° C. for 2 h. After cooling itwas concentrated under reduced pressure. The residue was purified byflash chromatography on a silica gel column with ethyl acetate inhexanes (0-50%) to afford the desired product (0.35 g). LCMS(M+H)⁺=253.0.

Step 2:(2S)-1-{4-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-1H-pyrazol-1-yl}propan-2-ol

A mixture of6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[4,3-c]pyridine(15 mg, 0.033 mmol) (Example 28, Step 4),(2S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propan-2-ol(10 mg, 0.04 mmol),[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complexedwith dichloromethane (1:1) (2 mg, 0.003 mmol), and potassium phosphate(14 mg, 0.067 mmol) in 1,4-dioxane (0.3 mL) and water (0.05 mL) in areaction vial was degassed and sealed. It was stirred at 90° C.overnight. After cooling it was diluted with methanol, purified byRP-HPLC (pH=2) to afford the desired product (2.5 mg) as TFA salt. LCMS(M+H)⁺=448.1.

Example 525-[6-(2,6-Difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-2-ethylisoindolin-1-one

Step 1: 6-(3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridine

A mixture of 6-chloro-1H-pyrazolo[4,3-c]pyridine (500 mg, 3.2 mmol)(Frontier Cat. No. Z13659), (3,5-dimethoxyphenyl)boronic acid (890 mg,4.9 mmol) (TCI Cat. No. D3513),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexedwith dichloromethane (1:1) (200 mg, 0.3 mmol), and sodium carbonate (1.0g, 9.8 mmol) in 1,2-dimethoxyethane (4 mL) and water (0.6 mL) wasdegassed, and sealed. The mixture was stirred at 110° C. overnight.After cooling it was partitioned between ethyl acetate and water. Afterseparation the aqueous solution was extracted with ethyl acetate twice.The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by flashchromatography on a silica gel column with ethyl acetate in hexanes(0-50%) to afford the desired product (0.80 g). LCMS (M+H)⁺=256.0.

Step 2: 6-(3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[4,3-c]pyridine

A mixture of 6-(3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridine (0.80 g,3.1 mmol) and N-iodosuccinimide (0.78 g, 3.4 mmol) inN,N-dimethylformamide (10 mL) was stirred at r.t. over weekend. Waterwas added to the mixture with stirring. The light brown solidprecipitated and was collected by filtration to afford the desiredproduct (0.83 g) which was directly used in next step reaction withoutfurther purification. LCMS (M+H)⁺=382.0.

Step 3:6-(3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine

A mixture of 6-(3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[4,3-c]pyridine(0.50 g, 1.3 mmol), dihydropyran (360 μL, 3.9 mmol), and methanesulfonicacid (17 μL, 0.26 mmol) in tetrahydrofuran (3 mL) and methylene chloride(7.5 mL) was stirred at 80° C. for 2 days. After cooling, to the mixturewas added some triethylamine, and concentrated under reduced pressure.The residue was purified by flash chromatography on a silica gel columnwith ethyl acetate in hexanes (0-50%) to afford the desired product(0.55 g). LCMS (M+H)⁺=466.0.

Step 4:6-(2-fluoro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine

1-(Chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octaneditetrafluoroborate (0.84 g, 2.4 mmol) (Alfa Aesar Cat. No. L17003) wasadded to a stirring solution of6-(3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine(0.55 g, 1.2 mmol) in acetonitrile (15 mL). The mixture was stirred atr.t. for 1 h. The solid was filtered out. The filtrate was concentratedunder reduced pressure. The residue was purified by flash chromatographyon a silica gel column with ethyl acetate in hexanes (0-50%) to affordthe desired product (0.52 g) which contained some amount of thecorresponding di-fluoride analogue, and was directly used in next stepreaction without further purification. LCMS (M+H)⁺=484.0

Step 5:6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine

1-(Chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octaneditetrafluoroborate (97 mg, 0.27 mmol) was added a stirring solution of6-(2-fluoro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine(88 mg, 0.18 mmol) in acetonitrile (5 mL). The mixture was stirred atr.t. for 1 h then concentrated. The solid was filtered out and thefiltrate was purified by flash chromatography on a silica gel columnwith ethyl acetate in hexanes (0-50%) to afford the desired product (30mg). LCMS (M+H)⁺=502.0.

Step 6: 5-bromo-2-ethylisoindolin-1-one

A mixture of methyl 4-bromo-2-(bromomethyl)benzoate (0.5 g, 2 mmol)(AstaTech Cat. No. 27012), ethylamine in THF (1.0 mL, 2.0 M) (AldrichCat. No. 395072), and potassium carbonate (0.34 g, 2.4 mmol) in ethanol(5 mL) in a sealed vial was stirred at 40° C. overnight. The solid wasfiltered off. The filtrate was concentrated under reduced pressure. Theresidue was purified by flash chromatography on a silica gel column withethyl acetate in hexanes (0-50%) to afford the desired product (0.28 g).LCMS (M+H)⁺=240.0/242.0.

Step 7:2-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one

A mixture of 5-bromo-2-ethylisoindolin-1-one (300 mg, 1.2 mmol),4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl] (310 mg,1.2 mmol) (Aldrich Cat. No. 473294), potassium acetate (300 mg, 3.1mmol), and [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II)complexed with dichloromethane (1:1) (30 mg, 0.04 mmol) in 1,4-dioxane(10 mL) was degassed and stirred at 100° C. for 3 h. After cooling itwas concentrated under reduced pressure. The residue was purified byflash chromatography on a silica gel column with ethyl acetate inhexanes (0-50%) to afford the desired product (0.26 g). LCMS(M+H)⁺=288.2.

Step 8:5-[6-(2,6-difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-2-ethylisoindolin-1-one

A mixture of6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine(9 mg, 0.02 mmol),2-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one(7.7 mg, 0.027 mmol),[1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) complexwith dichloromethane (1:1) (1 mg, 0.001 mmol), and sodium carbonate (5.7mg, 0.054 mmol) in 1,4-dioxane (0.2 mL) and water (0.03 mL) was degassedand recharged with nitrogen three times. The mixture was stirred at 110°C. for 3 h. After cooling the solid was filtered off. The filtrate wasconcentrated. The residue was dissolved in methanol (0.5 mL). At r.t. tothe solution was added HCl solution prepared previously from acetylchloride (0.30 mL) and methanol (0.30 mL). The mixture was stirred atr.t. for 2 h., and purified by RP-HPLC (pH=10) to afford the desiredproduct (5.6 mg). LCMS (M+H)⁺=451.1.

Example 535-[6-(2,6-Difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-2-isopropylisoindolin-1-one

Step 1: 5-bromo-2-isopropylisoindolin-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 52, Step 6 starting from4-bromo-2-(bromomethyl)benzoate (AstaTech Cat. No. 27012) andisopropylamine (Aldrich Cat No. 471291). LCMS (M+H)⁺=254.0/256.0.

Step 2:2-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 52, Step 7 starting from5-bromo-2-isopropylisoindolin-1-one and4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl]. LCMS(M+H)⁺=302.2.

Step 3:5-[6-(2,6-difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-2-isopropylisoindolin-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 52, Step 8 starting from6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridineand2-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one.LCMS (M+H)⁺=465.2.

Example 542-Cyclopropyl-5-[6-(2,6-difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]isoindolin-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 52, Step 8 starting from6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridineand2-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one(Example 21, Step 2) LCMS (M+H)+=463.2.

Example 553-[6-(2,6-Difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-6-ethyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one

Step 1: methyl 5-bromo-3-(bromomethyl)pyridine-2-carboxylate

Methyl 5-bromo-3-methylpyridine-2-carboxylate (800 mg, 3.5mmol)(Combi-Blocks Cat. No. SS-3016) in methylene chloride (15 mL) wastreated with N-bromosuccinimide (620 mg, 3.5 mmol) and AIBN[2,2′-azobis(isobutyronitrile)] (14 mg, 0.087 mmol). The mixture wasstirred and irradiated with a 250W tungsten halogen lamp overnight. LCMSshowed most starting material was consumed. The mixture wasconcentration under reduced pressure. The residue was purified by flashchromatography on a silica gel column with ethyl acetate in hexanes(0-50%) to afford the desired product (1.0 g). LCMS (M+H)⁺=309.9.

Step 2: 3-bromo-6-ethyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one

A mixture of methyl 5-bromo-3-(bromomethyl)pyridine-2-carboxylate (0.39g, 1.3 mmol), ethylamine in THF (0.88 mL, 2.0 M, 1.8 mmol) and potassiumcarbonate (0.26 g, 1.9 mmol) in ethanol (5 mL) in a sealed reaction vialwas stirred at 40° C. for 2 h. The solid was filtered off. The filtratewas concentrated under reduced pressure. The residue was purified byflash chromatography on a silica gel column with ethyl acetate inhexanes (0-50%) to afford the desired product (0.24 g). LCMS(M+H)⁺=240.9/242.9.

Step 3: (6-ethyl-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)boronicacid

A mixture of 3-bromo-6-ethyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one(240 mg, 1.0 mmol),4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl] (250 mg,1.0 mmol), potassium acetate (290 mg, 3.0 mmol), and[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complexedwith dichloromethane (1:1) (30 mg, 0.04 mmol) in 1,4-dioxane (10 mL) wasdegassed and stirred at 100° C. for 6 h. After cooling it wasconcentrated under reduced pressure. The residue was purified by flashchromatography on a silica gel column with ethyl acetate in hexanes(0-50%) to afford the desired product (0.11 g). LCMS (M+H)⁺=207.1.

Step 4:3-[6-(2,6-difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-6-ethyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 52, Step 8 starting from6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridineand (6-ethyl-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)boronicacid. LCMS (M+H)⁺=452.1.

Example 566-[6-(2,6-Difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-3,4-dihydroisoquinolin-1(2H)-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 52, Step 8 starting from6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridineand6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-1(2H)-one(Example 8, Step 1). LCMS (M+H)⁺=437.2.

Example 576-[6-(2,6-Difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-N,N-dimethylchromane-2-carboxamide

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 52, Step 8 starting from6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridineandN,N-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chromane-2-carboxamide(Example 2, Step 2). LCMS (M+H)⁺=495.4.

Example 585-[6-(2,6-Difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-2-(2-methoxyethyl)isoindolin-1-one

Step 1: 5-bromo-2-(2-methoxyethyl)isoindolin-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 52, Step 6 starting from4-bromo-2-(bromomethyl)benzoate (AstaTech Cat. No. 27012) and2-methoxyethylamine (Aldrich Cat No. 241067). LCMS (M+H)⁺=270.0/272.0.

Step 2:2-(2-methoxyethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 52, Step 7 starting from5-bromo-2-(2-methoxyethyl)isoindolin-1-one and4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl]. LCMS(M+H)⁺=318.1.

Step 3:5-[6-(2,6-difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-2-(2-methoxyethyl)isoindolin-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 52, Step 8 starting from6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridineand2-(2-methoxyethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one.LCMS (M+H)⁺=481.2.

Example 595-[6-(2,6-Difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-2-(tetrahydro-2H-pyran-4-yl)isoindolin-1-one

Step 1: 5-bromo-2-(tetrahydro-2H-pyran-4-yl)isoindolin-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 52, Step 6 starting from4-bromo-2-(bromomethyl)benzoate (AstaTech Cat. No. 27012) and4-aminotetrahydropyran (Aldrich Cat No. 711357). LCMS(M+H)⁺=296.0/298.0.

Step 2:2-(tetrahydro-2H-pyran-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 52, Step 7 starting from5-bromo-2-(tetrahydro-2H-pyran-4-yl)isoindolin-1-one and4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl]. LCMS(M+H)⁺=344.2.

Step 3:5-[6-(2,6-difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-2-(tetrahydro-2H-pyran-4-yl)isoindolin-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 52, Step 8 starting from6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridineand2-(tetrahydro-2H-pyran-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one.LCMS (M+H)⁺=507.2.

Example 605-[6-(2,6-Difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)isoindolin-1-one

Step 1: 5-bromo-2-(2,2,2-trifluoroethyl)isoindolin-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 52, Step 6 starting from4-bromo-2-(bromomethyl)benzoate and 2,2,2-trifluoroethylamine (AldrichCat No. 269042). LCMS (M+H)⁺=294.0/296.0.

Step 2:5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethyl)isoindolin-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 52, Step 7 starting from5-bromo-2-(2,2,2-trifluoroethyl)isoindolin-1-one and4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl]. LCMS(M+H)⁺=342.2.

Step 3:5-[6-(2,6-difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)isoindolin-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 52, Step 8 starting from6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridineand5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethyl)isoindolin-1-one.LCMS (M+H)⁺=505.0.

Example 615-[6-(2,6-Difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-2-(cis-4-hydroxycyclohexyl)isoindolin-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 52, Step 8 starting from5-[6-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-2-(tetrahydro-2H-pyran-4-yl)isoindolin-1-oneand2-(cis-4-hydroxycyclohexyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one(Example 16, Step 2). LCMS (M+H)⁺=521.2.

Example 625-[6-(2,6-Difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-2-(trans-4-hydroxycyclohexyl)isoindolin-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 52, Step 8 starting from5-[6-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-2-(tetrahydro-2H-pyran-4-yl)isoindolin-1-oneand2-(trans-4-hydroxycyclohexyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one(Example 15, Step 2). LCMS (M+H)⁺=521.2.

Example 635-[6-(2,6-Difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-2-(2-hydroxy-1-methylethyl)isoindolin-1-one

Step 1: 5-bromo-2-(2-hydroxy-1-methylethyl)isoindolin-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 52, Step 6 starting from4-bromo-2-(bromomethyl)benzoate and 2-aminopropanol (Aldrich Cat No.192171). LCMS (M+H)⁺=270.1.

Step 2:2-(2-hydroxy-1-methylethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 52, Step 7 starting from5-bromo-2-(2-hydroxy-1-methylethyl)isoindolin-1-one and4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl]. LCMS(M+H)⁺=318.1.

Step 3:5-[6-(2,6-difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-2-(2-hydroxy-1-methylethyl)isoindolin-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 52, Step 8 starting from6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridineand2-(2-hydroxy-1-methylethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one.LCMS (M+H)⁺=481.1.

Example 645-[6-(2,6-Difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-2-(2-hydroxypropyl)isoindolin-1-one

Step 1: 5-bromo-2-(2-hydroxypropyl)isoindolin-1-one

This compound was prepared using procedures analogous to those describedfor the synthesis of Example 52, Step 6 starting from4-bromo-2-(bromomethyl)benzoate and 1-amino-2-propanol (Aldrich Cat No.110248). LCMS (M+H)⁺=270.0/272.0.

Step 2:2-(2-hydroxypropyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one

This compound was prepared using procedures analogous to those describedfor the synthesis of Example 52, Step 7 starting from5-bromo-2-(2-hydroxypropyl)isoindolin-1-one and4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl]. LCMS(M+H)⁺=318.1.

Step 3:5-[6-(2,6-difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-2-(2-hydroxypropyl)isoindolin-1-one

This compound was prepared using procedures analogous to those describedfor the synthesis of Example 52, Step 8 starting from6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridineand2-(2-hydroxypropyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one.LCMS (M+H)⁺=481.1.

Example 655-[6-(2,6-Difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-6-fluoro-2-isopropylisoindolin-1-one

Step 1: Methyl 4-bromo-2-(bromomethyl)-5-fluorobenzoate

A mixture of methyl 4-bromo-5-fluoro-2-methylbenzoate (1.0 g, 4.0 mmol)(Ellanoval Laboratories Cat. No. 38-0304), N-bromosuccinimide (900. mg,5.06 mmol) and benzoyl peroxide (50 mg, 0.2 mmol) in carbontetrachloride (50 mL) was refluxed under a nitrogen atmosphere for 4 h.After cooling the mixture was diluted with methylene chloride. Theorganic solution was washed with brine, then dried over Na₂SO₄. Afterfiltration the filtrate was concentrated under reduced pressure. Theresidue was purified by flash chromatography on a silica gel column withethyl acetate in hexanes (0-50%) to afford the desired product (1.2 g).

Step 2: 5-bromo-6fluoro-2-isopropylisoindolin-1-one

This compound was prepared using procedures analogous to those describedfor the synthesis of Example 52, Step 6 starting from methyl4-bromo-2-(bromomethyl)-5-fluorobenzoate and isopropylamine. LC/MS:(M+H)⁺=271.9/273.9.

Step 3: (6-fluoro-2-isopropyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl)boronicacid

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 52, Step 7 starting from5-bromo-6-fluoro-2-isopropylisoindolin-1-one and4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl]. LCMS:(M+H)⁺=238.1.

Step 4:5-[6-(2,6-difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-6-fluoro-2-isopropylisoindolin-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 52, Step 8 starting from6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridineand (6-fluoro-2-isopropyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl)boronicacid. LCMS (M+H)⁺=483.1.

Example 665-[6-(2,6-Difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-2-(1-methylpiperidin-4-yl)isoindolin-1-one

Step 1: 5-bromo-2-(1-methylpiperidin-4-yl)isoindolin-1-one

A mixture of methyl 4-bromo-2-(bromomethyl)benzoate (0.3 g, 1 mmol;AstaTech Cat. No. 27012), 1-methylpiperidin-4-amine (0.14 g, 1.3mmol)(Combi-blocks Cat. No. 4003460), and potassium carbonate (0.19 g,1.4 mmol) in ethanol (5 mL) in a sealed reaction vial was stirred at 80°C. for 1 h. After cooling the solid was filtered off. The filtrate wasconcentrated under reduced pressure. The residue was purified by flashchromatography on a silica gel column with ethyl acetate in hexanes(0-50%) to afford the desired product (0.1 g). LCMS (M+H)⁺=309.0/311.0.

Step 2:2-(1-methylpiperidin-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 52, Step 7 starting from5-bromo-2-(1-methylpiperidin-4-yl)isoindolin-1-one and4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl]. LCMS(M+H)⁺=357.3.

Step 3:5-[6-(2,6-difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-2-(1-methylpiperidin-4-yl)isoindolin-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 52, Step 8 starting from6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridineand2-(1-methylpiperidin-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one.LCMS (M+H)⁺=520.2.

Example 675-[6-(2,6-Difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-2-[2-(dimethylamino)ethyl]isoindolin-1-one

Step 1: 5-bromo-2-[2-(dimethylamino)ethyl]isoindolin-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 52, Step 6 starting from4-bromo-2-(bromomethyl)benzoate and N,N-dimethylethylenediamine (AldrichCat No. D158003). LCMS (M+H)⁺=283.1.

Step 2:2-[2-(dimethylamino)ethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 52, Step 7 starting from5-bromo-2-[2-(dimethylamino)ethyl]isoindolin-1-one and4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl]. LCMS(M+H)⁺=331.3.

Step 3:5-[6-(2,6-difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-2-[2-(dimethylamino)ethyl]isoindolin-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 52, Step 8 starting from6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridineand2-[2-(dimethylamino)ethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one.LCMS (M+H)⁺=494.3.

Example 685-[6-(2,6-Difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-2-[2-(1-methylpyrrolidin-2-yl)ethyl]isoindolin-1-one

Step 1: 5-bromo-2-[2-(1-methylpyrrolidin-2-yl)ethyl]isoindolin-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 52, Step 6 starting from4-bromo-2-(bromomethyl)benzoate and 2-(2-aminoethyl)-1-methylpyrrolidine(Aldrich Cat No. D139505). LCMS (M+H)⁺=323.0.

Step 2:2-[2-(1-methylpyrrolidin-2-yl)ethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 52, Step 7 starting from5-bromo-2-[2-(1-methylpyrrolidin-2-yl)ethyl]isoindolin-1-one and4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl]. LCMS(M+H)⁺=371.3.

Step 3:5-[6-(2,6-difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-2-[2-(1-methylpyrrolidin-2-yl)ethyl]isoindolin-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 52, Step 8 starting from6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridineand2-[2-(1-methylpyrrolidin-2-yl)ethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one.LCMS (M+H)⁺=534.3.

Example 695-[6-(2-chloro-6-fluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-2-ethylisoindolin-1-one

Step 1:6-(2-chloro-6-fluoro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine

At r.t. to a solution of6-(2-fluoro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine(35 mg, 0.072 mmol) (Example 52, Step 4) in methylene chloride (3 mL)was added sulfuryl chloride (7.0 μL, 0.087 mmol). The mixture wasstirred at r.t. for 20 min then concentrated. The solid was filtered outand the crude material was purified by flash chromatography on a silicagel column with ethyl acetate in hexanes (0-50%) to afford the desiredproduct (0.025 g). LCMS (M+H)⁺=518.1.

Step 2:5-[6-(2-chloro-6-fluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-2-ethylisoindolin-1-one

This compound was prepared using procedures analogous to those describedin Example 52, Step 8 starting from6-(2-chloro-6-fluoro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridineand2-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one.LCMS (M+H)⁺=466.1.

Example 706-(2,6-dichloro-3,5-dimethoxyphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine

Step 1: 6-(3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-b]pyridine

A mixture of 6-bromo-1H-pyrazolo[4,3-b]pyridine (0.3 g, 2 mmol;)(AnnovaChem Cat. No. L05238), (3,5-dimethoxyphenyl)boronic acid (0.33 g, 1.8mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)complexed with dichloromethane (1:1) (100 mg, 0.1 mmol), and potassiumphosphate (0.64 g, 3.0 mmol) in 1,4-dioxane (1 mL) and water (0.12 mL)was degassed and sealed. It was stirred at 85° C. overnight. Aftercooling it was concentrated under reduced pressure. The residue waspurified by flash chromatography on a silica gel column with ethylacetate in hexanes (0-50%) to afford the desired product (0.38 g). LCMS(M+H)⁺=256.2.

Step 2: 6-(3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[4,3-b]pyridine

At r.t. to a solution of6-(3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-b]pyridine (0.38 g, 1.5 mmol) inmethylene chloride (5 mL) was added N-iodosuccinimide (0.352 g, 1.56mmol) with stirring. The mixture was stirred at r.t. overnight. Then thesolvent was removed, the residue was treated with methanol. The solidwas collected by filtration to afford the desired product (0.54 g) whichwas directly used in next step reaction without further purification.LCMS (M+H)⁺=382.1.

Step 3:6-(3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridine

A mixture of 6-(3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[4,3-b]pyridine(0.54 g, 1.4 μmmol), dihydropyran (0.39 mL, 4.2 mmol) andmethanesulfonic acid (18 μL, 0.28 mmol) in methylene chloride (6 mL) andtetrahydrofuran (2 mL) in a sealed reaction vial was stirred at 50° C.for 3 h. After cooling it was concentrated under reduced pressure. Theresidue was purified by flash chromatography on a silica gel column withethyl acetate in hexanes (0-50%) to afford the desired product (0.60 g).LCMS (M+H)⁺=465.9.

Step 4:6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridine

Sulfuryl chloride (0.20 mL, 2.4 mmol) was added drop-wise to stirring asolution of6-(3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridine(0.60 g, 1.3 mmol) in methylene chloride (10 mL). The mixture wasstirred at r.t. for 2 h. LCMS showed about 30% product formed and 70%mono-chlorinated product formed. To the mixture another 70 μL ofsulfuryl chloride was added. The mixture was stirred at r.t. for anadditional 3 h then concentrated under reduced pressure. The residue waspurified by flash chromatography on a silica gel column with ethylacetate in hexanes (0-50%) to afford the desired product (0.56 g). LCMS(M+H)⁺=533.9.

Step 5:6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine

A mixture of6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridine(25 mg, 0.047 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (12mg, 0.056 mmol), tetrakis(triphenylphosphine)palladium(0) (3 mg, 0.002mmol), and cesium carbonate (46 mg, 0.14 mmol) in 1,4-dioxane (0.5 mL)and water (0.07 mL) in a reaction vial was degassed, sealed, and stirredat 85° C. for 3 h. After cooling the mixture was concentrated and theresidue was dissolved in methanol (0.4 mL, 10 mmol). To the solution wasadded HCl solution previously prepared from acetyl chloride (0.3 mL) inmethanol (0.3 mL). The mixture was stirred at r.t. for 1 h thenconcentrated, diluted with methanol, and purified by RP-HPLC (pH=2) toafford the desired product (3.9 mg) as a TFA salt. LCMS (M+H)⁺=404.1.

Example 713-{4-[6-(2,6-Dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-b]pyridin-3-yl]-1H-pyrazol-1-yl}propan-1-ol

Step 1:6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-(1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridine

A mixture of6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridine(60 mg, 0.1 mmol), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate(40. mg, 0.13 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexedwith dichloromethane (1:1) (7 mg, 0.009 mmol), and potassium phosphate(48 mg, 0.22 mmol) in 1,4-dioxane (0.5 mL) and water (0.07 mL) in areaction vial was degassed and sealed. It was stirred at 85° C.overnight. After cooling it was concentrated under reduced pressure. Theresidue was purified by flash chromatography on a silica gel column withethyl acetate in hexanes (0-50%) to afford the desired product (50 mg).

Step 2:3-{4-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-b]pyridin-3-yl]-1H-pyrazol-1-yl}propan-1-ol

A mixture of 3-bromo-1-propanol (5.7 μL, 0.063 mmol),6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-(1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridine(15 mg, 0.032 mmol), and cesium carbonate (14 mg, 0.044 mmol) inacetonitrile (0.5 mL) was stirred at 50° C. for 2 h. After cooling thesolid was filtered out and washed with acetonitrile. The filtrate wasconcentrated and the residue was dissolved in methanol (0.3 mL). To thesolution was added 0.5 mL of HCL solution previously prepared fromacetyl chloride (0.25 mL) and methanol (0.25 mL). The mixture wasstirred at r.t. for 2 h. It was concentrated and the resulting residuewas dissolved in methanol, and purified by RP-HPLC (pH=2) to afford thedesired product as TFA salt. LCMS (M+H)⁺=448.0.

Example 726-(2,6-Difluoro-3,5-dimethoxyphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-b]pyridine

Step 1: 6-chloro-3-iodo-1H-pyrazolo[3,4-b]pyridine

A mixture of 6-chloro-1H-pyrazolo[3,4-b]pyridine (0.40 g, 2.6 mmol)(ArkPharm Cat. No. AK-32412) and N-iodosuccinimide (0.64 g, 2.9 mmol) inmethylene chloride (6 mL) and acetonitrile (3 mL) was stirred at 70° C.for 3 h. After cooling it was concentrated and the residue was treatedwith water. The precipitate was collected by filtration to afford thedesired product (0.70 g). LCMS (M+H)⁺=279.9.

Step 2:6-chloro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine

A mixture of 6-chloro-3-iodo-1H-pyrazolo[3,4-b]pyridine (0.70 g, 2.5mmol), dihydropyran (690 μL, 7.5 mmol) and methanesulfonic acid (33 μL,0.50 mmol) in methylene chloride (30 mL) and tetrahydrofuran (10 mL) inreaction flask was stirred at r.t. overnight. It was concentrated underreduced pressure. The residue was purified by flash chromatography on asilica gel column with ethyl acetate in hexanes (0-50%) to afford thedesired product (0.80 g). LCMS (M-84+H)⁺=279.9.

Step 3:6-chloro-3-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine

A mixture of6-chloro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine(200 mg, 0.6 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(110 mg, 0.55 mmol), tetrakis(triphenylphosphine)palladium(0) (30 mg,0.03 mmol), and cesium carbonate (540 mg, 1.6 mmol) in 1,4-dioxane (1mL) and water (0.12 mL) was degassed and sealed. It was stirred at 80°C. for 3 h. After cooling it was concentrated under reduced pressure.The residue was purified by flash chromatography on a silica gel columnwith ethyl acetate in hexanes (0-50%) to afford the desired product(0.12 g). LCMS (M+H)⁺=318.0.

Step 4:6-(3,5-dimethoxyphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine

A mixture of (3,5-dimethoxyphenyl)boronic acid (0.13 g, 0.71 mmol),6-chloro-3-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine(0.15 g, 0.47 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexedwith dichloromethane (1:1) (30 mg, 0.04 mmol) and potassium phosphate(200 mg, 0.94 mmol) in 1,4-dioxane (1.0 mL) and water (0.13 mL) in areaction vial was degassed and sealed. The mixture was stirred at 90° C.for 2 h. After cooling it was concentrated under reduced pressure. Theresidue was purified by flash chromatography on a silica gel column withethyl acetate in hexanes (0-50%) to afford the desired product (180 mg).LCMS (M+H)⁺=420.1.

Step 5:6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-b]pyridine

At r.t. to a stirring solution of6-(3,5-dimethoxyphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine(40 mg, 0.1 mmol) in acetonitrile (3 mL) was added1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octaneditetrafluoroborate (68 mg, 0.19 mmol). The mixture was stirred at 40°C. for 40 min. After cooling it was treated with methanol. Afterconcentration, the residue was treated with methanol, the solid wasfiltered off. The filtrate was concentrated. The residue was dissolvedin methanol (1 mL). To the solution was added HCl solution previouslyprepared from acetyl chloride (0.5 mL) and methanol (0.5 mL). Themixture was stirred at r.t. for 30 min. The product was purified byRP-HPLC (pH=10) to afford the desired product. LCMS (M+H)⁺=372.2.

Example 732-{4-[6-(2,6-Dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-1H-pyrazol-1-yl}propanenitrile

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 4, Step 2 starting from6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidineand2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propanenitrile(Example 34, Step 1). LCMS (M+H)⁺=444.0/446.0. ¹H NMR (300 MHz, DMSO-d₆)δ: 9.72 (s, 1H), 8.72 (s, 1H), 8.33 (s, 1H), 7.04 (s, 1H), 5.92 (q,J=7.1 Hz, 1H), 3.97 (s, 6H), 1.88 (d, J=7.1 Hz, 3H).

Example 742-Cyclopropyl-5-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]isoindolin-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 4, Step 2 starting from6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidineand2-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one.LCMS (M+H)⁺=496.0/498.0

Example 756-(2,6-Dichloro-3,5-dimethoxyphenyl)-3-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrazolo[3,4-d]pyrimidine

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 4, Step 2 starting from6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidineand1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine(Alfa Aesar, Cat. No. H51659). LCMS (M+H)⁺=499.1/501.1. ¹H NMR (300 MHz,DMSO-d₆) δ: 9.61 (s, 1H), 7.91 (d, J=8.8 Hz, 2H), 7.01 (d, J=8.8 Hz,2H), 6.98 (s, 1H), 3.92 (s, 6H), 3.30-3.14 (m, 8H), 2.17 (s, 3H).

Example 762-{4-[6-(2,6-Difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-1H-pyrazol-1-yl}propanenitrile

This compound was prepared as a TFA salt by using procedures analogousto those described for the synthesis of Example 7, Step 3 starting from6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidineand2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propanenitrile.LCMS (M+H)⁺=412.0.

Example 773-[6-(2,6-Dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-6-ethyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one

This compound was prepared as a TFA salt by using procedures analogousto those described for the synthesis of Example 1, Step 7 starting from6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidineand6-ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one(Example 55, Step 3). LCMS (M+H)⁺=485.0/487.0.

Example 785-[6-(2,6-Difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-isopropylisoindolin-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 1, Step 7 starting from6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidineand2-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one.LCMS (M+H)+=466.0.

Example 795-[6-(2,6-Difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-(1-methylpiperidin-4-yl)isoindolin-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 4, Step 2 starting from6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidineand2-(1-methylpiperidin-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one.LCMS (M+H)⁺=521.1. ¹H NMR (300 MHz, DMSO-d₆) δ: 14.57 (s, 1H), 9.86 (s,1H), 8.39 (s, 1H), 8.27 (d, J=8.0 Hz, 1H), 7.82 (d, J=8.0 Hz, 1H), 7.18(t, J=8.2 Hz, 1H), 4.58 (s, 2H), 3.94 (s, 6H), 2.92-2.84 (m, 5H), 2.21(s, 3H), 2.08-1.66 (m, 4H).

Example 805-[6-(2,6-Difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-[2-(dimethylamino)ethyl]isoindolin-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 4, Step 2 starting from6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidineand2-[2-(dimethylamino)ethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one.LCMS (M+H)⁺=495.1.

Example 815-[6-(2,6-Difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-(2-hydroxy-1-methylethyl)isoindolin-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 4, Step 2 starting from6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidineand2-(2-hydroxy-1-methylethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one.LCMS (M+H)⁺=482.0.

Example 825-[6-(2,6-Difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-(2-hydroxypropyl)isoindolin-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 4, Step 2 starting from6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidineand2-(2-hydroxypropyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one.LCMS (M+H)⁺=482.1.

Example 835-[6-(2,6-Difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-N,N-dimethyl-2,3-dihydro-1-benzofuran-2-carboxamide(Enantiomer I)

A mixture of6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine(17.9 mg, 0.0357 mmol) (Example 52, Step 5),N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1-benzofuran-2-carboxamide(13.6 mg, 0.0429 mmol) (Peak I from chiral separation, Example 4, Step1), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)complexed with dichloromethane (1:1) (0.0018 g, 0.0021 mmol), andpotassium phosphate (0.0228 g, 0.107 mmol) in 1,4-dioxane (0.48 mL) andwater (0.24 mL) in a reaction vial was sealed, and degassed andrecharged with nitrogen three times. The mixture was stirred at 90° C.for 3 h. After cooling, the mixture was diluted with ethyl acetate (2mL). The mixture was filtered. The filtrate was concentrated underreduced pressure. The residue was dissolved in methanol (0.3 mL). To thesolution was added a solution of acetyl chloride (0.2 mL) in methanol(0.2 mL) which was previously prepared at 0° C. The mixture was stirredat r.t. for 2 h., diluted with methanol, and purified by RP-HPLC (pH=2)to afford the desired product as a TFA salt. LCMS (M+H)⁺=481.0. ¹H NMR(300 MHz, DMSO-d₆) δ: 13.62 (s, 1H), 9.47 (d, J=1.1 Hz, 1H), 7.95 (s,1H), 7.86 (d, J=8.4 Hz, 1H), 7.70 (s, 1H), 7.12 (t, J=8.2 Hz, 1H), 6.97(d, J=8.4 Hz, 1H), 5.81-5.70 (m, 1H), 3.93 (s, 6H), 3.57-3.48 (m, 2H),3.13 (s, 3H), 2.90 (s, 3H).

Example 845-[6-(2,6-Difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-N,N-dimethyl-2,3-dihydro-1-benzofuran-2-carboxamide(Enantiomer II)

This compound was prepared as a TFA salt by using procedures analogousto those described for the synthesis of Example 83 starting from6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine(Example 52, Step 5) andN,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1-benzofuran-2-carboxamide(Peak II from chiral separation, Example 4, Step 1). LCMS (M+H)⁺=481.0.

Example 857-[6-(2,6-Difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline

Step 1: tert-butyl7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

This compound was prepared as by using procedures analogous to thosedescribed for the synthesis of Example 1, Step 2 starting fromtert-butyl 7-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate and4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl]. LCMS(M+H-56)⁺=304.1.

Step 2: tert-butyl7-[6-(2,6-difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-3,4-dihydroisoquinoline-2(1H)-carboxylate

A mixture of6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine(16.7 mg, 0.0400 mmol), tert-butyl7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(17.96 mg, 0.05000 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1) (2.0 mg, 0.0024 mmol) and potassium phosphate(25.5 mg, 0.120 mmol) in 1,4-dioxane (0.50 mL) and water (0.15 mL) in areaction vial was sealed, and degassed and recharged with nitrogen forthree times. The mixture was stirred at 115° C. for 3 h. After cooling,the mixture was diluted with methanol, and purified by RP-HPLC (pH=10)to afford the desired product. LCMS (M+H)⁺=524.1.

Step 3:7-[6-(2,6-difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline

tert-Butyl7-[6-(2,6-difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-3,4-dihydroisoquinoline-2(1H)-carboxylate(10.0 mg, 0.0191 mmol) in dichloromethane (0.10 mL) was treated with TFA(0.10 mL). The mixture was stirred at r.t. for 1 h. The volatiles wereevaporated. The residue was dissolved in acetonitrile (0.5 mL) andN,N-diisopropylethylamine (30.0 μL). To the mixture was addedmethanesulfonyl chloride (2.0 μL, 0.026 mmol). The mixture was stirredat r.t. for 30 min, and then diluted with methanol, and purified byRP-HPLC (pH=10) to afford the desired product. LCMS (M+H)⁺=502.1.

Example 866-(2,6-Dichloro-3,5-dimethoxyphenyl)-3-(2,3-dihydro-1-benzofuran-5-yl)-1H-pyrazolo[3,4-d]pyrimidine

This compound was prepared as TFA salt by using procedures analogous tothose described for the synthesis of Example 7, Step 3 starting from6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidineand 2,3-dihydro-1-benzofuran-5-ylboronic acid. LCMS (M+H)⁺=443.0/445.0.

Example 876-(2,6-Difluoro-3,5-dimethoxyphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidine

This compound was prepared as a TFA salt by using procedures analogousto those described for the synthesis of Example 7, Step 3 starting from6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidineand1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.LCMS (M+H)⁺=373.0. ¹H NMR (300 MHz, DMSO-d₆) δ: 14.11 (s, 1H), 9.74 (s,1H), 8.56 (s, 1H), 8.17 (s, 1H), 7.17 (t, J=8.1 Hz, 1H), 3.95 (s, 3H),3.93 (s, 3H).

Example 882-{4-[6-(2,6-Difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-1H-pyrazol-1-yl}ethanol

Step 1:1-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.20 g, 1.0 mmol) (Aldrich Cat. No. 525057),2-(2-bromoethoxy)tetrahydro-2H-pyran (170 μL, 1.1 mmol) (Aldrich Cat.No. 475394) and potassium carbonate (0.21 g, 1.5 mmol) in acetonitrile(2 mL) was stirred at r.t. overnight. After filtration the filtrate wasconcentrated under reduced pressure. The residue was purified by flashchromatography on a silica gel column with ethyl acetate in hexanes(0-50%) to afford the desired product.

Step 2:2-{4-[6-(2,6-difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-1H-pyrazol-1-yl}ethanol

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 52, Step 8 starting from6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridineand1-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.LCMS (M+H)⁺=402.1.

Example 895-[6-(2-Chloro-6-fluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-2-cyclopropylisoindolin-1-one

Step 1:5-[6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-2-cyclopropylisoindolin-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 72, Step 3 starting from6-chloro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine(Example 72, Step 2) and2-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one.LCMS (M+H)⁺=409.1.

Step 2:2-cyclopropyl-5-[6-(3,5-dimethoxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl]isoindolin-1-one

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 72, Step 4 starting from5-[6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-2-cyclopropylisoindolin-1-oneand 2-(3,5-dimethoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.LCMS (M+H)⁺=511.2.

Step 3:2-cyclopropyl-5-[6-(2-fluoro-3,5-dimethoxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl]isoindolin-1-one

1-(Chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octaneditetrafluoroborate (0.21 g, 0.59 mmol) was added to a stirring solutionof2-cyclopropyl-5-[6-(3,5-dimethoxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl]isoindolin-1-one(0.15 g, 0.29 mmol) in acetonitrile (3 mL). The mixture was stirred atr.t. for 2 h. Then it was concentrated under reduced pressure. Theresidue was purified by flash chromatography on a silica gel column withethyl acetate in hexanes (0-50%) to afford the desired product (0.12 g).LCMS (M+H)⁺=529.2.

Step 4:5-[6-(2-chloro-6-fluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-2-cyclopropylisoindolin-1-one

Sulfuryl chloride (10. μL, 0.12 mmol) was added to a stirring solutionof2-cyclopropyl-5-[6-(2-fluoro-3,5-dimethoxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl]isoindolin-1-one(65 mg, 0.12 mmol) in methylene chloride (1 mL). The mixture was stirredat r.t. for 30 min. It was concentrated to dryness. The solid wasdissolved in methanol (0.3 mL). To the solution was added a solution ofHCl previously prepared from acetyl chloride (0.15 mL) and methanol(0.15 mL). The mixture was stirred at r.t. for 1 h and then diluted withmethanol, and purified by RP-HPLC (pH=10) to afford the desired product.LCMS (M+H)⁺=479.1.

Example 906-(2,6-Dichloro-3,5-dimethoxyphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine

Step 1: 6-chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine

A mixture of 6-chloro-1H-pyrazolo[4,3-c]pyridine (0.3 g, 2 mmol)(Frontier Cat. No. Z13659) and N-iodosuccinimide (0.53 g, 2.3 mmol) inN,N-dimethylformamide (2 mL) was stirred at 80° C. for 1 h. Aftercooling it was concentrated and the residue was treated with methanol.The white solid was collected by filtration to afford the desiredproduct (0.5 g). LCMS (M+H)⁺=279.9.

Step 2:6-chloro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine

At r.t. to a suspension of 6-chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine(0.55 g, 2.0 mmol) in methylene chloride (6 mL) and tetrahydrofuran (3mL) was added methanesulfonic acid (20 μL, 0.4 mmol), followed bydihydropyran (0.54 mL, 5.9 mmol) (Aldrich, Cat. #: D106208). The mixturewas stirred at r.t. overnight. Then, it was stirred at 60° C. for 4 h.After cooling it was concentrated under reduced pressure. The residuewas purified by flash chromatography on a silica gel column with ethylacetate in hexanes (0-50%) to afford the desired product (0.72 g).

Step 3:6-chloro-3-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine

A mixture of6-chloro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine(120 mg, 0.33 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(100 mg, 0.50 mmol), tetrakis(triphenylphosphine)palladium(0) (20 mg,0.02 mmol) and cesium carbonate (320 mg, 0.99 mmol) in 1,4-dioxane (1mL) and water (0.12 mL) was degassed and sealed. It was stirred at 85°C. for 3 h. After cooling it was concentrated under reduced pressure.The residue was purified by flash chromatography on a silica gel columnwith ethyl acetate in hexanes (0-50%) to afford the desired product(0.10 g). LCMS (M+H)⁺=318.1.

Step 4:6-(3,5-dimethoxyphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine

A mixture of6-chloro-3-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine(0.06 g, 0.2 mmol),2-(3,5-dimethoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.060g, 0.23 mmol),[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complexwith dichloromethane (1:1) (10 mg, 0.02 mmol), and potassium phosphate(80. mg, 0.38 mmol) in 1,4-dioxane (0.5 mL) and water (0.07 mL) in areaction vial was degassed and sealed. The mixture was stirred at 90° C.for 2 h. After cooling it was concentrated under reduced pressure. Theresidue was purified by flash chromatography on a silica gel column withethyl acetate in hexanes (0-50%) to afford the desired product (80 mg).LCMS (M+H)⁺=420.2.

Step 5:6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine

At 0° C. to a stirring solution of6-(3,5-dimethoxyphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine(80 mg, 0.2 mmol) in methylene chloride (3 mL) was added dropwise asolution of sulfuryl chloride (31 μL, 0.38 mmol)(Acros Organics, Cat. #:37815) in methylene chloride (1 mL). The mixture was stirred at r.t.overnight. To the mixture was added acetonitrile (2 mL) and it wasstirred at r.t. for 1 h. Then, to the mixture was added another 31 μL ofsulfuryl chloride and it was stirred at r.t. for 4 h. The solvent wasremoved under reduced pressure and the residue was treated withmethylene chloride and sat'd NaHCO₃ solution. After separation the aq.layer was extracted with methylene chloride. The combined organic layerswere dried over Na₂SO₄. After filtration the filtrate was concentratedunder reduced pressure. The residue was purified by flash chromatographyon a silica gel column with ethyl acetate in hexanes (0-50%) to affordan intermediate which was dissolved in methanol (3 mL), and cooled to 0°C. To the solution was added a pre-cooled HCl solution prepared fromacetyl chloride (700 μL, 10 mmol) and methanol (1 mL). The mixture wasstirred at r.t. for 4 h and then the solvents were removed. The residuewas dissolved in methanol, and purified by RP-HPLC (pH=2) to afford thedesired product (4.8 mg) as a TFA salt. LCMS (M+H)⁺=404.1.

Example 916-(2,6-Difluoro-3,5-dimethoxyphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine

At 0° C. to a stirring solution of6-(3,5-dimethoxyphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine(70 mg, 0.2 mmol) in acetonitrile (1 mL) was added a suspension of1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octaneditetrafluoroborate (120 mg, 0.33 mmol) in acetonitrile (2 mL). Themixture was stirred at r.t. for 3 h. To the mixture another portion of1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octaneditetrafluoroborate (100 mg) was added and then the mixture was stirredat r.t. overnight. Then another portion of1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octaneditetrafluoroborate (60 mg) was added. The mixture was stirred at 40° C.for 1 h. After cooling it was treated with sat′d NaHCO₃ solution andfiltered. After filtration the filtrate was concentrated to dryness andthe residue was dissolved in methanol. At r.t. to the mixture was addedHCl solution previously prepared from acetyl chloride (0.5 mL) andmethanol (0.5 mL). The mixture was stirred at r.t. for 1 h. and purifiedby RP-HPLC (pH=10) to afford the desired product 0.8 mg. LCMS(M+H)⁺=372.2. ¹H-NMR (500 MHz, DMSO-d₆) δ: 9.31 (s, 1H), 8.39 (s, 1H),8.03 (s, 1H), 7.54 (s, 1H), 7.06 (t, J=8.0 Hz, 1H), 3.93 (s, 3H), 3.90(s, 6H).

Example 92 Methyl5-[6-(2,6-difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-1-benzofuran-2-carboxylate

Step 1: ethyl5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-benzofuran-2-carboxylate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 52, Step 7 starting from ethyl(5-bromobenzofuran)-2-carboxylate (Maybridge Cat. No. CC 31223) and4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl] (AldrichCat. No. 473294).

Step 2: methyl5-[6-(2,6-difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-1-benzofuran-2-carboxylate

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 52, Step 8 starting from6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine(9 mg, 0.02 mmol; from step 6) and ethyl5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-benzofuran-2-carboxylate.LCMS (M+H)⁺: m/z=466.2.

Example 936-(2,6-Difluoro-3,5-dimethoxyphenyl)-3-imidazo[1,2-a]pyridin-6-yl-1H-pyrazolo[3,4-d]pyrimidine

This compound was prepared by using procedures analogous to thosedescribed for the synthesis of Example 4, Step 2 starting from6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine(16.7 mg, 0.0400 mmol)(Example 3, Step 4) andimidazo[1,2-a]pyridin-6-ylboronic acid (Combi-Blocks, Cat. No. BB-3457).LCMS (M+H)⁺=409.0.

Example 946-[6-(2,6-Difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]quinoline

This compound was prepared using procedures analogous to those describedfor the synthesis of Example 4, Step 2 starting from6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidineand quinolin-6-ylboronic acid (Combi-Blocks, Cat. No. BB-5182). LCMS(M+H)⁺=420.1.

Example A FGFR Enzymatic Assay

The inhibitor potency of the Example compounds was measured in an enzymeassay that measures peptide phosphorylation using FRET measurements todetect product formation. Inhibitors were serially diluted in DMSO and avolume of 0.5 μL was transferred to the wells of a 384-well plate. ForFGFR3, a 10 μL volume of FGFR3 enzyme (Millipore) diluted in assaybuffer (50 mM HEPES, 10 mM MgCl₂, 1 mM EGTA, 0.01% Tween-20, 5 mM DTT,pH 7.5) was added to the plate and pre-incubated for 5-10 minutes.Appropriate controls (enzyme blank and enzyme with no inhibitor) wereincluded on the plate. The assay was initiated by the addition of a 10μL solution containing biotinylated EQEDEPEGDYFEWLE peptide substrate(SEQ ID NO: 1) and ATP (final concentrations of 500 nM and 140 μMrespectively) in assay buffer to the wells. The plate was incubated at25° C. for 1 hr. The reactions were ended with the addition of 10μL/well of quench solution (50 mM Tris, 150 mM NaCl, 0.5 mg/mL BSA,pH˜7.8, 30 mM EDTA with Perkin Elmer Lance Detection Reagents at 3.75 nMEu-antibody PY20 and 180 nM APC-Streptavidin). The plate was allowed toequilibrate for 1 hour before scanning the wells on a PheraStar platereader (BMG Labtech). The enzymes were purchased from Millipore orInvitrogen.

FGFR1 and FGFR2 were measured under equivalent conditions with thefollowing changes in enzyme and ATP concentrations: FGFR1, 0.02 nM and210 μM, respectively and FGFR2, 0.01 nM and 100 μM, respectively.

GraphPad prism3 was used to analyze the data. The IC₅₀ values werederived by fitting the data to the equation for a sigmoidaldose-response with a variable slope. Y=Bottom+(Top−Bottom)/(1+10̂((LogIC₅₀−X)*HillSlope)) where X is the logarithm of concentration and Y isthe response. Compounds having an IC₅₀ of 1 μM or less are consideredactive.

The compounds of the Examples were found to be inhibitors of one or moreof FGFR1, FGFR2, and FGFR3 according to the above-described assay. IC₅₀data is provided below in Table 1. The symbol “+” indicates an IC₅₀ lessthan 100 nM and the symbol “++” indicates an IC₅₀ of 100 to 500 nM.

TABLE 1 Example FGFR1 FGFR2 FGFR3 No. IC50 (nM) IC50 (nM) IC50 (nM)1 + + + 2 + + + 3 + + + 4 + + + 5 + + + 6 + + + 7 + + + 8 + + + 9 + + +10 + + + 11 + + + 12 + + + 13 + + + 14 + + + 15 + + + 16 + + + 17 + + +18 + + + 19 + + + 20 + + + 21 + + + 22 + + + 23 + + + 24 + + + 25 + + +26 + + + 27 + + + 28 + + + 29 + + + 30 + + + 31 + ++ + 32 + + + 33 + + +34 + + + 35 + + + 36 + + + 37 + + + 38 + + + 39 + + + 40 + + + 41 + + +42 + + + 43 + + + 44 + + + 45 + + + 46 + + + 47 + + + 48 + + + 49 + + +50 + + + 51 + + + 52 + + + 53 + + + 54 + + + 55 + + + 56 + + + 57 + + +58 + + + 59 + + + 60 + + + 61 + + + 62 + + + 63 + + + 64 + + + 65 + + +66 + + + 67 + + + 68 + + + 69 + + + 70 + + + 71 + + + 72 + + + 73 + + +74 + + + 75 + + + 76 + + + 77 + + + 78 + + + 79 + + + 80 + + + 81 + + +82 + + + 83 + + + 84 + + + 85 + + + 86 + + + 87 + + + 88 + + + 89 + + +90 + + + 91 + + + 92 + + + 93 + + + 94 + + +

Example B FGFR3 Cell Proliferation/Survival Assays

A recombinant cell line over-expressing human FGFR3 was developed bystable transfection of the mouse pro-B Ba/F3 cells (obtained from theDeutsche Sammlung von Mikroorganismen and Zellkulturen) with a plasmidencoding the full length human FGFR3. Cells were sequentially selectedfor puromycin resistance and proliferation in the presence of heparinand FGF1. A single cell clone was isolated and characterized forfunctional expression of FGFR3. This Ba/F3-FGFR3 clone is used in cellproliferation assays, and compounds are screened for their ability toinhibit cell proliferation/survival. The Ba/F3-FGFR3 cells are seededinto 96 well, black cell culture plates at 3500 cells/well in RPMI1640media containing 2% FBS, 20 ug/mL Heparin and 5 ng/mL FGF1. The cellswere treated with 10 μL of 10× concentrations of serially dilutedcompounds (diluted with medium lacking serum from 5 mM DSMO dots) to afinal volume of 100 μL/well. After 72 hour incubation, 100 μL of CellTiter Glo® reagent (Promega Corporation) that measures cellular ATPlevels is added to each well. After 20 minute incubation with shaking,the luminescence is read on a plate reader. The luminescent readings areconverted to percent inhibition relative to DMSO treated control wells,and the IC₅₀ values are calculated using GraphPad Prism software.Compounds having an IC₅₀ of 10 μM or less are considered active. Othernon-recombinant cancer cell lines representing a variety of tumor typesincluding KMS-11 (multiple myeloma), RT112 (bladder cancer), KatoIII(gastric cancer), and H-1581 (lung) are used in similar proliferationassays. In some experiments, MTS reagent, Cell Titer 96® AQueous OneSolution Reagent (Promega Corporation) is added to a final concentrationof 333 μg/mL in place Cell Titer Glo and read at 490/650 nm on a platereader. Compounds having an IC₅₀ of 5 μM or less are considered active.

Example C Cell-Based FGFR Phosphorylation Assays

The inhibitory effect of compounds on FGFR phosphorylation in relevantcell lines (Ba/F3-FGFR3, KMS-11, RT112, KatoIII, H-1581 cancer celllines and HUVEC cell line) can be assessed using immunoassays specificfor FGFR phosphorylation. Cells are starved in media with reduced serum(0.5%) and no FGF1 for 4 to 48 h depending upon the cell line thentreated with various concentrations of individual inhibitors for 1-4hours. For some cell lines, such as Ba/F3-FGFR3 and KMS-11, cells arestimulated with Heparin (20 μg/mL) and FGF1 (10 ng/mL) for 10 min. Wholecell protein extracts are prepared by incubation in lysis buffer withprotease and phosphatase inhibitors [50 mM HEPES (pH 7.5), 150 mM NaCl,1.5 mM MgCl₂, 10% Glycerol, 1% Triton X-100, 1 mM sodium orthovanadate,1 mM sodium fluoride, aprotinin (2 μg/mL), leupeptin (2 μg/mL),pepstatin A (2 μg/mL), and phenylmethylsulfonyl fluoride (1 mM)] at 4°C. Protein extracts are cleared of cellular debris by centrifugation at14,000×g for 10 minutes and quantified using the BCA (bicinchoninicacid) microplate assay reagent (Thermo Scientific).

Phosphorylation of FGFR receptor in protein extracts was determinedusing immunoassays including western blotting, enzyme-linked immunoassay(ELISA) or bead-based immunoassays (Luminex). For detection ofphosphorylated FGFR2, a commercial ELISA kit DuoSet IC Human Phospho-FGFR2a ELISA assay (R&D Systems, Minneapolis, Minn.) can be used. For theassay KATOlll cells are plated in 0.2% FBS supplemented Iscove's medium(50,000 cells/well/per 100 μL) into 96-well flat-bottom tissue culturetreated plates (Corning, Corning, N.Y.), in the presence or absence of aconcentration range of test compounds and incubated for 4 hours at 37°C., 5% CO₂. The assay is stopped with addition of 200 μL of cold PBS andcentrifugation. The washed cells are lysed in Cell Lysis Buffer (CellSignaling, #9803) with Protease Inhibitor (Calbiochem, #535140) and PMSF(Sigma, #P7626) for 30 min on wet ice. Cell lysates were frozen at −80°C. before testing an aliquot with the DuoSet IC Human Phospho-FGF R2aELISA assay kit. GraphPad prism3 was used to analyze the data. The IC₅₀values were derived by fitting the data to the equation for a sigmoidaldose-response with a variable slope.

For detection of phosphorylated FGFR3, a bead based immunoassay wasdeveloped. An anti-human FGFR3 mouse mAb (R&D Systems, cat#MAB7661) wasconjugated to Luminex MAGplex microspheres, bead region 20 and used asthe capture antibody. RT-112 cells were seeded into multi-well tissueculture plates and cultured until 70% confluence. Cells were washed withPBS and starved in RPMI+0.5% FBS for 18 hr. The cells were treated with10 μL of 10× concentrations of serially diluted compounds for 1 hr at37° C., 5% CO₂ prior to stimulation with 10 ng/mL human FGF1 and 20μg/mL Heparin for 10 min. Cells were washed with cold PBS and lysed withCell Extraction Buffer (Invitrogen) and centrifuged. Clarifiedsupernatants were frozen at −80° C. until analysis.

For the assay, cell lysates are diluted 1:10 in Assay Diluent andincubated with capture antibody-bound beads in a 96-well filter platefor 2 hours at room temperature on a plate shaker. Plates are washedthree times using a vacuum manifold and incubated with anti-phospho-FGFR1-4 (Y653/Y654) rabbit polyclonal antibody (R&D Systems cat# AF3285)for 1 hour at RT with shaking Plates are washed three times. The dilutedreporter antibody, goat anti-rabbit-RPE conjugated antibody (InvitrogenCat. # LHB0002) is added and incubated for 30 minutes with shakingPlates are washed three times. The beads are suspended in wash bufferwith shaking at room temperature for 5 minutes and then read on aLuminex 200 instrument set to count 50 events per sample, gate settings7500-13500. Data is expressed as mean fluorescence intensity (MFI). MFIfrom compound treated samples are divided by MFI values from DMSOcontrols to determine the percent inhibition, and the IC₅₀ values arecalculated using the GraphPad Prism software. Compounds having an IC₅₀of 1 μM or less are considered active.

Example D FGFR Cell-Based Signaling Assays

Activation of FGFR leads to phosphorylation of Erk proteins. Detectionof pErk is monitored using the Cellu'Erk HTRF (Homogeneous Time ResolvedFlurorescence) Assay (CisBio) according to the manufacturer's protocol.KMS-11 cells are seeded into 96-well plates at 40,000 cells/well in RPMImedium with 0.25% FBS and starved for 2 days. The medium is aspiratedand cells are treated with 30 μL of 1× concentrations of seriallydiluted compounds (diluted with medium lacking serum from 5 mM DSMOdots) to a final volume of 30 μL/well and incubated for 45 min at roomtemperature. Cells are stimulated by addition of 10 μL of Heparin (100μg/mL) and FGF1 (50 ng/mL) to each well and incubated for 10 min at roomtemperature. After lysis, an aliquot of cell extract is transferred into384-well low volume plates, and 4 μL of detection reagents are addedfollowed by incubation for 3 hr at room temperature. The plates are readon a PheraStar instrument with settings for HTRF. The normalizedfluorescence readings are converted to percent inhibition relative toDMSO treated control wells, and the IC₅₀ values are calculated using theGraphPad Prism software. Compounds having an IC₅₀ of 1 μM or less areconsidered active.

Example E VEGFR2 Kinase Assay

40 μL Enzyme reactions are run in black 384 well polystyrene plates for1 hour at 25° C. Wells are dotted with 0.8 μL of test compound in DMSO.The assay buffer contains 50 mM Tris, pH˜7.5, 0.01% Tween-20, 10 mMMgCl₂, 1 mM EGTA, 5 mM DTT, 0.5 μM Biotin-labeled EQEDEPEGDYFEWLEpeptide substrate (SEQ ID NO: 1), 1 mM ATP, and 0.1 nM enzyme (Milliporecatalogue number 14-630). Reactions are stopped by addition of 20 μLStop Buffer (50 mM Tris, pH=7.8, 150 mM NaCl, 0.5 mg/mL BSA, 45 mM EDTA)with 225 nM LANCE Streptavidin Surelight® APC (PerkinElmer cataloguenumber CR130-100) and 4.5 nM LANCE Eu-W1024 anti phosphotyrosine (PY20)antibody (PerkinElmer catalogue number AD0067). After 20 minutes ofincubation at room temperature, the plates are read on a PheraStar FSplate reader (BMG Labtech). IC₅₀ values can be calculated using GraphPadPrism. Compounds having an IC₅₀ of 1 μM or less are considered active.

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference, including all patent,patent applications, and publications, cited in the present applicationis incorporated herein by reference in its entirety.

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein: W is N or CR⁶; Yis N or CR⁷; Z is N or CR⁸; wherein one or two of W, Y, and Z is N; L isabsent or selected from C₂₋₆ alkenylene, C₃₋₆ heteroalkenylene, C₂₋₆alkynylene, and C₃₋₆ heteroalkynylene, wherein said C₂₋₆ alkenylene,C₃₋₆ heteroalkenylene, C₂₋₆ alkynylene, and C₃₋₆ heteroalkynylene areeach optionally substituted with 1, 2, or 3 substituents independentlyselected from halo, CN, NO₂, OR^(a), C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄cyanoalkyl, C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d),NR^(c)R^(d), NR^(c)C(O)R^(b), NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d),C(═NR^(e))R^(b), C(═NR^(e))NR^(c)R^(d), NR^(c)C(═NR^(e))NR^(c)R^(d),NR^(c)S(O)R^(b), NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), and S(O)₂NR^(c)R^(d); A is selected fromFormulas [aa], [bb], and [cc]:

rings B and C in Formula [aa] together form a fused bicyclicheterocycle, wherein ring B is a six-membered aromatic ring selectedfrom phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, andtriazinyl, wherein ring C is a 5- or 6-membered carbocycle or a 5- or6-membered heterocycle, wherein 0, 1, or 2 ring-forming carbon ornitrogen atoms in ring C can be substituted by oxo, and wherein thefused bicyclic heterocycle comprising rings B and C is attached to L inFormula I via a ring atom in ring B; Q¹, Q², and Q³ are eachindependently selected from N and CH, wherein at least one of Q¹, Q²,and Q³ is CH; each R^(X) is a substituent on ring B and is independentlyselected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, and C₁₋₄ cyanoalkyl;each R^(Y) is a substituent on ring C and is independently selected fromC₁₋₆ alkyl, C₁₋₆ haloalkyl, Cy¹, OR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1),C(O)OR^(a1), C(═NR^(e1))R^(b1), C(═NR^(e1))NR^(c1)R^(d1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1), wherein saidC₁₋₆ alkyl, is optionally substituted with 1, 2, 3, 4, or 5 substituentsindependently selected from R^(Ya); each R^(Ya) is independentlyselected from Cy¹, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, CN, NO₂, OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1),C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1), C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)S(O)R^(b1),NR^(c1)S(O)₂R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1), wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl of R^(Ya) are each optionallysubstituted with 1, 2, or 3 substituents independently selected fromCy¹, halo, CN, NO₂, OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1),C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1), C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)S(O)R^(b1),NR^(c1)S(O)₂R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1); each R^(A) isindependently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, Cy², CN, NO₂, OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2),C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2),NR^(c2)C(O)R^(b2), NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2),C(═NR^(e2))R^(b2), C(═NR^(e2))NR^(c2)R^(d2),NR^(c2)C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2),NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2),and S(O)₂NR^(c2)R^(d2); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl are each optionally substituted with 1, 2, 3, 4, or 5substituents independently selected from R^(AZ); each R^(AZ) isindependently selected from Cy², halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a2), SR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2),C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)C(═NR^(e2))NR^(c2)R^(d2),NR^(c2)R^(d2), NR^(c2)C(O)R^(b2), NR^(c2)C(O)OR^(a2),NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2),NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2),and S(O)₂NR^(c2)R^(d2), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl of R^(AZ) are each optionally substituted with 1, 2, or 3substituents independently selected from Cy², halo, CN, NO₂, OR^(a2),SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), C(═NR^(e2))NR^(c2)R^(d2),NR^(c2)C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)S(O)R^(b2),NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2); R^(B1) is H,C₁₋₆ alkyl, Cy³, C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3),C(═NR^(e3))R^(b3), or C(═NR^(e3))NR^(c3)R^(d3); wherein said C₁₋₆ alkyl,is optionally substituted with 1, 2, 3, 4, or 5 substituentsindependently selected from R^(BZ); each R^(BZ) is independentlyselected from Cy³, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, CN, NO₂, OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3),C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)S(O)R^(b3),NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3), wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl of R^(BZ) are each optionallysubstituted with 1, 2, or 3 substituents independently selected fromCy³, halo, CN, NO₂, OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3),C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)S(O)R^(b3),NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3); each R^(B2) isindependently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, Cy³, CN, NO₂, OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3),C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3),NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3),C(═NR^(e3))R^(b3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)S(O)R^(b3), NR^(c3)S(O)₂R^(b3),NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3),and S(O)₂NR^(c3)R^(d3); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl are each optionally substituted with 1, 2, 3, 4, or 5substituents independently selected from R^(BZ); R¹, R², R⁴, and R⁵ areeach independently selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, CN,OR^(a4), SR^(a4), C(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)S(O)R^(b4), NR^(c4)S(O)₂R^(b4), S(O)R^(b4), S(O)NR^(c4)R^(d4),S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4); wherein said C₁₋₄ alkyl isoptionally substituted with 1, 2, or 3 substituents independentlyselected from halo, CN, OR^(a4), SR^(a4), C(O)NR^(c4)R^(d4),NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)S(O)R^(b4), NR^(c4)S(O)₂R^(b4),S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4); R³is H, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, CN, OR^(a4), SR^(a4),C(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)S(O)R^(b4),NR^(c4)S(O)₂R^(b4), S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4), andS(O)₂NR^(c4)R^(d4); wherein said C₁₋₄ alkyl is optionally substitutedwith 1, 2, or 3 substituents independently selected from halo, CN,OR^(a4), SR^(a4), C(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)S(O)R^(b4), NR^(c4)S(O)₂R^(b4), S(O)R^(b4), S(O)NR^(c4)R^(d4),S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4); R⁶, R⁷, and R⁸ are eachindependently selected from H, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, andC₁₋₄ cyanoalkyl; Cy¹, Cy², and Cy³ are each independently selected fromC₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, each of which is optionally substituted by 1, 2, 3, 4,or 5 substituents independently selected from halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, NO₂,OR^(a5), SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5),OC(O)R^(b5), OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)OR^(a5), NR^(c5)C(O)NR^(c5)R^(d5), C(═NR^(e5))R^(b5),C(═NR^(e5))NR^(c5)R^(d5), NR^(c5)C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)S(O)R^(b5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5),S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are eachoptionally substituted with 1, 2, or 3 substituents independentlyselected from halo, C₁₋₄ haloalkyl, CN, NO₂, OR^(a5), SR^(a5),C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5),OC(O)NR^(c5)R^(d5), C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)C(═NR^(e5))NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)OR^(a5), NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)S(O)R^(b5),NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), S(O)R^(b5),S(O)NR^(c5)R^(d5), S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5); each R^(a),R^(b), R^(c), R^(d), R^(a1), R^(b1), R^(c1), R^(d1), R^(a2), R^(b2),R^(c2), R^(d2), R^(a3), R^(b3), R^(c3), R^(d3), R^(a5), R^(b5), R^(c5),R^(d5) is independently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, (5-10 membered heteroaryl)-C₁₋₄ alkyl, or (4-10membered heterocycloalkyl)-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, (5-10 membered heteroaryl)-C₁₋₄ alkyl, and (4-10membered heterocycloalkyl)-C₁₋₄ alkyl is optionally substituted with 1,2, 3, 4, or 5 substituents independently selected from C₁₋₄ alkyl, C₁₋₄haloalkyl, halo, CN, OR^(a6), SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6),C(O)OR^(a6), OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6),NR^(c6)C(O)R^(b6), NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6),C(═NR^(e6))NR^(c6)R^(d6), NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), and S(O)₂NR^(c6)R^(d6); each R^(a4), R^(b4),R^(c4), and R^(d4) is independently selected from H, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ hydroxyalkyl, and C₁₋₄ cyanoalkyl; or any R^(c) andR^(d) together with the N atom to which they are attached form a 4-, 5-,6-, or 7-membered heterocycloalkyl group optionally substituted with 1,2, or 3 substituents independently selected from C₁₋₆ alkyl, C₃₋₇cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 memberedheteroaryl, C₁₋₆ haloalkyl, halo, CN, OR^(a6), SR^(a6), C(O)R^(b6),C(O)NR^(c6)R^(d6), C(O)OR^(a6), OC(O)R^(b6), OC(O)NR^(c6)R^(d6),NR^(c6)R^(d6), NR^(c6)C(O)R^(b6), NR^(c6)C(O)NR^(c6)R^(d6),NR^(c6)C(O)OR^(a6), C(═NR^(e6))NR^(c6)R^(d6),NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), S(O)R^(b6), S(O)NR^(c6)R^(d6),S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6), NR^(c6)S(O)₂NR^(c6)R^(d6), andS(O)₂NR^(c6)R^(d6), wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl areoptionally substituted by 1, 2, or 3 substituents independently selectedfrom halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, CN, OR^(a6),SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6), OC(O)R^(b6),OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6), C(═NR^(e6))NR^(c6)R^(d6),NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), S(O)R^(b6), S(O)NR^(c6)R^(d6),S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6), NR^(c6)S(O)₂NR^(c6)R^(d6), andS(O)₂NR^(c6)R^(d6); or any R^(c1) and R^(d1) together with the N atom towhich they are attached form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3substituents independently selected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl,3-7 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆haloalkyl, halo, CN, OR^(a6), SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6),C(O)OR^(a6), OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6),NR^(c6)C(O)R^(b6), NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6),C(═NR^(e6))NR^(c6)R^(d6), NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), and S(O)₂NR^(c6)R^(d6), wherein said C₁₋₆alkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, and5-6 membered heteroaryl are optionally substituted by 1, 2, or 3substituents independently selected from halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ cyanoalkyl, CN, OR^(a6), SR^(a6), C(O)R^(b6),C(O)NR^(c6)R^(d6), C(O)OR^(a6), OC(O)R^(b6), OC(O)NR^(c6)R^(d6),NR^(c6)R^(d6), NR^(c6)C(O)R^(b6), NR^(c6)C(O)NR^(c6)R^(d6),NR^(c6)C(O)OR^(a6), C(═NR^(e6))NR^(c6)R^(d6),NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), S(O)R^(b6), S(O)NR^(c6)R^(d6),S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6), NR^(c6)S(O)₂NR^(c6)R^(d6), andS(O)₂NR^(c6)R^(d6); or any R^(c2) and R^(d2) together with the N atom towhich they are attached form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3substituents independently selected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl,4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl,C₁₋₆ haloalkyl, halo, CN, OR^(a6), SR^(a6), C(O)R^(b6),C(O)NR^(c6)R^(d6), C(O)OR^(a6), OC(O)R^(b6), OC(O)NR^(c6)R^(d6),NR^(c6)R^(d6), NR^(c6)C(O)R^(b6), NR^(c6)C(O)NR^(c6)R^(d6),NR^(c6)C(O)OR^(a6), C(═NR^(e6))NR^(c6)R^(d6),NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), S(O)R^(b6), S(O)NR^(c6)R^(d6),S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6), NR^(c6)S(O)₂NR^(c6)R^(d6), andS(O)₂NR^(c6)R^(d6), wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl areoptionally substituted by 1, 2, or 3 substituents independently selectedfrom halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, CN, OR^(a6),SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6), OC(O)R^(b6),OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6), C(═NR^(e6))NR^(c6)R^(d6),NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), S(O)R^(b6), S(O)NR^(c6)R^(d6),S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6), NR^(c6)S(O)₂NR^(c6)R^(d6), andS(O)₂NR^(c6)R^(d6); or any R^(c3) and R^(d3) together with the N atom towhich they are attached form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3substituents independently selected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl,4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆haloalkyl, halo, CN, OR^(a6), SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6),C(O)OR^(a6), OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6),NR^(c6)C(O)R^(b6), NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6),C(═NR^(e6))NR^(c6)R^(d6), NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), and S(O)₂NR^(c6)R^(d6), wherein said C₁₋₆alkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, and5-6 membered heteroaryl are optionally substituted by 1, 2, or 3substituents independently selected from halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ cyanoalkyl, CN, OR^(a6), SR^(a6), C(O)R^(b6),C(O)NR^(c6)R^(d6), C(O)OR^(a6), OC(O)R^(b6), OC(O)NR^(c6)R^(d6),NR^(c6)R^(d6), NR^(c6)C(O)R^(b6), NR^(c6)C(O)NR^(c6)R^(d6),NR^(c6)C(O)OR^(a6), C(═NR^(e6))NR^(c6)R^(d6),NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), S(O)R^(b6), S(O)NR^(c6)R^(d6),S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6), NR^(c6)S(O)₂NR^(c6)R^(d6), andS(O)₂NR^(c6)R^(d6); or any R^(c5) and R^(d5) together with the N atom towhich they are attached form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3substituents independently selected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl,4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆haloalkyl, halo, CN, OR^(a6), SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6),C(O)OR^(a6), OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6),NR^(c6)C(O)R^(b6), NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6),C(═NR^(e6))NR^(c6)R^(d6), NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), and S(O)₂NR^(c6)R^(d6), wherein said C₁₋₆alkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, and5-6 membered heteroaryl are optionally substituted by 1, 2, or 3substituents independently selected from halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ cyanoalkyl, CN, OR^(a6), SR^(a6), C(O)R^(b6),C(O)NR^(c6)R^(d6), C(O)OR^(a6), OC(O)R^(b6), OC(O)NR^(c6)R^(d6),NR^(c6)R^(d6), NR^(c6)C(O)R^(b6), NR^(c6)C(O)NR^(c6)R^(d6),NR^(c6)C(O)OR^(a6), C(═NR^(e6))NR^(c6)R^(d6),NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), S(O)R^(b6), S(O)NR^(c6)R^(d6),S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6), NR^(c6)S(O)₂NR^(c6)R^(d6), andS(O)₂NR^(c6)R^(d6); each R^(a6), R^(b6), R^(c6), and R^(d6) isindependently selected from H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl,and C₂₋₄ alkynyl, wherein said C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄alkynyl, is optionally substituted with 1, 2, or 3 substituentsindependently selected from OH, CN, amino, halo, C₁₋₄ alkyl, C₁₋₄alkoxy, C₁₋₄ alkylthio, C₁₋₄ alkylamino, di(C₁₋₄ alkyl)amino, C₁₋₄haloalkyl, and C₁₋₄ haloalkoxy; or any R^(c6) and R^(d6) together withthe N atom to which they are attached form a 3-, 4-, 5-, 6-, or7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3substituents independently selected from OH, CN, amino, halo, C₁₋₆alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ alkylamino, di(C₁₋₄alkyl)amino, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy; and each R^(e),R^(e1), R^(e2), R^(e3), R^(e5), and R^(e6) is independently selectedfrom H, C₁₋₄ alkyl, and CN; n1 is 0, 1, 2, 3, 4, or 5; n2 is 0, 1, or 2;p is 0, 1, 2, or 3; and q is 0, 1, 2, or
 3. 2. The compound of claim 1,or a pharmaceutically acceptable salt thereof, wherein: W is CR⁶; Y isN; and Z is N.
 3. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein: W is CR⁶; Y is N; and Z is CR⁸.
 4. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein: W is CR⁶; Y is CR⁷; and Z is N.
 5. The compound of claim 1, ora pharmaceutically acceptable salt thereof, wherein: W is N; Y is CR⁷;and Z is CR⁸.
 6. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein L is absent.
 7. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein L is selectedfrom C₂₋₆ alkenylene, C₃₋₆ heteroalkenylene, C₂₋₆ alkynylene, and C₃₋₆heteroalkynylene, wherein said C₂₋₆ alkenylene, C₃₋₆ heteroalkenylene,C₂₋₆ alkynylene, and C₃₋₆ heteroalkynylene are each optionallysubstituted with 1, 2, or 3 substituents independently selected fromhalo, CN, NO₂, OR^(a), C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl,C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d),NR^(c)C(O)R^(b), NR^(c)(O)OR^(a), NR^(c)C(O)NR^(c)R^(d),C(═NR^(e))R^(b), C(═NR^(e))NR^(c)R^(d), NR^(c)C(═NR^(e))NR^(c)R^(d),NR^(c)S(O)R^(b), NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), and S(O)₂NR^(c)R^(d).
 8. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein L isselected from C₂₋₆ alkenylene and C₂₋₆ alkynylene, wherein said C₂₋₆alkenylene and C₂₋₆ alkynylene are each optionally substituted with 1,2, or 3 substituents independently selected from halo, CN, NO₂, OR^(a),C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, C(O)NR^(c)R^(d),C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d), C(═NR^(e))R^(b),C(═NR^(e))NR^(c)R^(d), NR^(c)C(═NR^(e))NR^(c)R^(d), NR^(c)S(O)R^(b),NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b), S(O)NR^(c)R^(d),S(O)₂R^(b), and S(O)₂NR^(c)R^(d).
 9. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein L is selected fromC₂₋₆ alkenylene and C₂₋₆ alkynylene.
 10. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R³ is H.
 11. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R¹, R², R⁴, and R⁵ are each independently selected from halo,C₁₋₄ alkyl, C₁₋₄ haloalkyl, CN, and OR^(a4).
 12. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein R¹, R², R⁴,and R⁵ are each independently selected from F, Cl, and methoxy.
 13. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R¹ and R⁵ are each independently selected from F and Cl, and R²and R⁴ are each methoxy.
 14. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R⁶, R⁷, and R⁸ areeach independently selected from H and halo.
 15. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein R⁶, R⁷, and R⁸are each H.
 16. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein A is a group represented by Formula[aa].
 17. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein Ring B is phenyl or pyridyl.
 18. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein Ring C is a5-membered carbocycle or a 5-membered heterocycle.
 19. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein Ring Cis a 6-membered carbocycle or a 6-membered heterocycle.
 20. The compoundof claim 1, or a pharmaceutically acceptable salt thereof, whereinFormula [aa] is a structure selected from:


21. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein each R^(Y) is independently selected from C₁₋₆ alkyl,Cy¹, C(O)NR^(c1)R^(d1), C(O)OR^(a1), and S(O)₂R^(b1), wherein said C₁₋₆alkyl is optionally substituted with halo, OR^(a1), NR^(c1)R^(d1), orCy¹.
 22. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein A is a group represented by Formula [bb].
 23. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein Q¹, Q², and Q³ are each CH.
 24. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein Q¹ is N and Q², and Q³are each CH.
 25. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein Q¹ and Q² are both CH and Q³ is N. 26.The compound of claim 1, or a pharmaceutically acceptable salt thereof,wherein each R^(A) is independently selected from halo, C₁₋₆ alkyl, Cy²,and OR^(a2); wherein said C₁₋₆ alkyl is optionally substituted with 1,2, or 3 substituents independently selected from R^(AZ).
 27. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein n1 is 0, 1, or
 2. 28. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein A is a grouprepresented by Formula [cc].
 29. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein A is a grouprepresented by Formula [cc1]:


30. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R^(B1) is C₁₋₆ alkyl optionally substituted with 1 or 2substituents independently selected from R^(BZ).
 31. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein eachR^(BZ) is independently selected from CN, OR^(a3), andC(O)NR^(c3)R^(d3).
 32. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein n2 is
 0. 33. The compound of claim 1,or a pharmaceutically acceptable salt thereof, having Formula IIa, IIb,IIc, or IId:

wherein R¹ and R⁵ are independently selected from F and Cl.
 34. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,selected from:5-[6-(2,6-Dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-N,N-dimethyl-2,3-dihydro-1-benzofuran-2-carboxamide;6-[6-(2,6-Dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-N,N-dimethylchromane-2-carboxamide;5-[6-(2,6-Difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-N,N-dimethyl-2,3-dihydro-1-benzofuran-2-carboxamide;5-[6-(2,6-Difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-N,N-dimethyl-2,3-dihydro-1-benzofuran-2-carboxamide;6-[6-(2,6-Difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-N,N-dimethylchromane-2-carboxamide;6-(2,6-Difluoro-3,5-dimethoxyphenyl)-3-{2-[(4-methylpiperazin-1-yl)carbonyl]-2,3-dihydro-1-benzofuran-5-yl}-1H-pyrazolo[3,4-d]pyrimidine;6-[6-(2,6-Dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-3,4-dihydroisoquinolin-1(2H)-one;6-[6-(2,6-Dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methyl-3,4-dihydroisoquinolin-1(2H)-one;6-[6-(2,6-Dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-ethyl-3,4-dihydroisoquinolin-1(2H)-one;6-[6-(2,6-Dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-isopropyl-3,4-dihydroisoquinolin-1(2H)-one;6-[6-(2,6-Difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-3,4-dihydroisoquinolin-1(2H)-one;6-[6-(2,6-Difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline;6-(2,6-Difluoro-3,5-dimethoxyphenyl)-3-[(4-methoxyphenyl)ethynyl]-1H-pyrazolo[3,4-d]pyrimidine;5-[6-(2,6-Difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-(trans-4-hydroxycyclohexyl)isoindolin-1-one;5-[6-(2,6-Difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-(cis-4-hydroxycyclohexyl)isoindolin-1-one;6-(2,6-Difluoro-3,5-dimethoxyphenyl)-3-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrazolo[3,4-d]pyrimidine;6-(2,6-Difluoro-3,5-dimethoxyphenyl)-3-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-1H-pyrazolo[3,4-d]pyrimidine;6-(2,6-Difluoro-3,5-dimethoxyphenyl)-3-[2-(4-methylpiperazin-1-yl)pyridin-4-yl]-1H-pyrazolo[3,4-d]pyrimidine;2-{4-[6-(2,6-Difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]phenoxy}-N,N-dimethylethanamine;2-Cyclopropyl-5-[6-(2,6-difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]isoindolin-1-one;5-[6-(2,6-Dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-(cis-4-hydroxycyclohexyl)isoindolin-1-one;5-[6-(2,6-Dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-(trans-4-hydroxycyclohexyl)isoindolin-1-one;6-(2,6-Difluoro-3,5-dimethoxyphenyl)-3-{2-[(4-methylpiperazin-1-yl)carbonyl]-2,3-dihydro-1-benzofuran-5-yl}-1H-pyrazolo[4,3-c]pyridine;6-(2,6-Difluoro-3,5-dimethoxyphenyl)-3-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrazolo[4,3-c]pyridine;6-(2,6-Difluoro-3,5-dimethoxyphenyl)-3-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-1H-pyrazolo[4,3-c]pyridine;6-(2,6-Difluoro-3,5-dimethoxyphenyl)-3-[2-(4-methylpiperazin-1-yl)pyridin-4-yl]-1H-pyrazolo[4,3-c]pyridine;2-Cyclopropyl-5-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]isoindolin-1-one;2-{4-[6-(2,6-Dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-2-methylphenoxy}-N,N-dimethylacetamide;6-[6-(2,6-Dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-2H-1,4-benzoxazin-3(4H)-one;6-[6-(2,6-Dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-4-methyl-2H-1,4-benzoxazin-3(4H)-one;5-[6-(2,6-Dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-2-benzofuran-1(3H)-one;2-{4-[6-(2,6-Dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-1H-pyrazol-1-yl}propanenitrile;2-{4-[6-(2,6-Dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-2-fluorophenyl}-2-hydroxy-N,N-dimethylacetamide;2-{4-[6-(2,6-Dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]phenoxy}-N,N-dimethylethanamine;2-{4-[6-(2,6-Dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-1H-pyrazol-1-yl}-N-methylacetamide;2-{4-[6-(2,6-Dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-1H-pyrazol-1-yl}-N,N-dimethylacetamide;N-Cyclopropyl-2-{4-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-1H-pyrazol-1-yl}acetamide;1-({4-[6-(2,6-Dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-1H-pyrazol-1-yl}acetyl)azetidin-3-ol;6-(2,6-Dichloro-3,5-dimethoxyphenyl)-3-[1-(2-morpholin-4-yl-2-oxoethyl)-1H-pyrazol-4-yl]-1H-pyrazolo[4,3-c]pyridine;6-(2,6-Dichloro-3,5-dimethoxyphenyl)-3-{1-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-1H-pyrazol-4-yl}-1H-pyrazolo[4,3-c]pyridine;2-{4-[6-(2,6-Dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-1H-pyrazol-1-yl}-N-(1-methylpiperidin-4-yl)acetamide;1-({4-[6-(2,6-Dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-1H-pyrazol-1-yl}acetyl)pyrrolidin-3-ol;1-({4-[6-(2,6-Dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-1H-pyrazol-1-yl}acetyl)-N,N-dimethylpyrrolidin-3-amine;6-(2,6-Dichloro-3,5-dimethoxyphenyl)-3-{1-[2-(3-methoxypyrrolidin-1-yl)-2-oxoethyl]-1H-pyrazol-4-yl}-1H-pyrazolo[4,3-c]pyridine;2-{4-[6-(2,6-Dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-1H-pyrazol-1-yl}-N-(2-methoxyethyl)acetamide;1-({4-[6-(2,6-Dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-1H-pyrazol-1-yl}acetyl)pyrrolidine-3-carbonitrile;6-(2,6-Dichloro-3,5-dimethoxyphenyl)-3-(1-{2-[(3S)-3-fluoropyrrolidin-1-yl]-2-oxoethyl}-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine;6-(2,6-Dichloro-3,5-dimethoxyphenyl)-3-[(E)-2-(1-methyl-1H-pyrazol-4-yl)vinyl]-1H-pyrazolo[4,3-c]pyridine;2-(4-{(E)-2-[6-(2,6-Dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]vinyl}-1H-pyrazol-1-yl)ethanol;(2S)-1-{4-[6-(2,6-Dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-1H-pyrazol-1-yl}propan-2-ol;5-[6-(2,6-Difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-2-ethylisoindolin-1-one;5-[6-(2,6-Difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-2-isopropylisoindolin-1-one;2-Cyclopropyl-5-[6-(2,6-difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]isoindolin-1-one;3-[6-(2,6-Difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-6-ethyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one;6-[6-(2,6-Difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-3,4-dihydroisoquinolin-1(2H)-one;6-[6-(2,6-Difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-N,N-dimethylchromane-2-carboxamide;5-[6-(2,6-Difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-2-(2-methoxyethyl)isoindolin-1-one;5-[6-(2,6-Difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-2-(tetrahydro-2H-pyran-4-yl)isoindolin-1-one;5-[6-(2,6-Difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)isoindolin-1-one;5-[6-(2,6-Difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-2-(cis-4-hydroxycyclohexyl)isoindolin-1-one;5-[6-(2,6-Difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-2-(trans-4-hydroxycyclohexyl)isoindolin-1-one;5-[6-(2,6-Difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-2-(2-hydroxy-1-methylethyl)isoindolin-1-one;5-[6-(2,6-Difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-2-(2-hydroxypropyl)isoindolin-1-one;5-[6-(2,6-Difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-6-fluoro-2-isopropylisoindolin-1-one;5-[6-(2,6-Difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-2-(1-methylpiperidin-4-yl)isoindolin-1-one;5-[6-(2,6-Difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-2-[2-(dimethylamino)ethyl]isoindolin-1-one;5-[6-(2,6-Difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-2-[2-(1-methylpyrrolidin-2-yl)ethyl]isoindolin-1-one;5-[6-(2-chloro-6-fluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-2-ethylisoindolin-1-one;6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine;3-{4-[6-(2,6-Dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-b]pyridin-3-yl]-1H-pyrazol-1-yl}propan-1-ol;6-(2,6-Difluoro-3,5-dimethoxyphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-b]pyridine;2-{4-[6-(2,6-Dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-1H-pyrazol-1-yl}propanenitrile;2-Cyclopropyl-5-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]isoindolin-1-one;6-(2,6-Dichloro-3,5-dimethoxyphenyl)-3-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrazolo[3,4-d]pyrimidine;2-{4-[6-(2,6-Difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-1H-pyrazol-1-yl}propanenitrile;3-[6-(2,6-Dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-6-ethyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one;5-[6-(2,6-Difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-isopropylisoindolin-1-one;5-[6-(2,6-Difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-(1-methylpiperidin-4-yl)isoindolin-1-one;5-[6-(2,6-Difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-[2-(dimethylamino)ethyl]isoindolin-1-one;5-[6-(2,6-Difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-(2-hydroxy-1-methylethyl)isoindolin-1-one;5-[6-(2,6-Difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-(2-hydroxypropyl)isoindolin-1-one;5-[6-(2,6-Difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-N,N-dimethyl-2,3-dihydro-1-benzofuran-2-carboxamide;7-[6-(2,6-Difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline;6-(2,6-Dichloro-3,5-dimethoxyphenyl)-3-(2,3-dihydro-1-benzofuran-5-yl)-1H-pyrazolo[3,4-d]pyrimidine;6-(2,6-Difluoro-3,5-dimethoxyphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidine;2-{4-[6-(2,6-Difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-1H-pyrazol-1-yl}ethanol;5-[6-(2-Chloro-6-fluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-2-cyclopropylisoindolin-1-one;6-(2,6-Dichloro-3,5-dimethoxyphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine;6-(2,6-Difluoro-3,5-dimethoxyphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine;Methyl5-[6-(2,6-difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-1-benzofuran-2-carboxylate;6-(2,6-Difluoro-3,5-dimethoxyphenyl)-3-imidazo[1,2-a]pyridin-6-yl-1H-pyrazolo[3,4-d]pyrimidine;and6-[6-(2,6-Difluoro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]quinolone.35. A pharmaceutical composition comprising a compound of claim 1, or apharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable carrier.
 36. A method of inhibiting an FGFRenzyme comprising contacting the FGFR enzyme with a compound of claim 1,or a pharmaceutically acceptable salt thereof.
 37. A method of treatingcancer in a patient comprising administering to said patient atherapeutically effective amount of a compound of claim 1, or apharmaceutically acceptable salt thereof.
 38. The method of claim 37wherein said cancer is selected from bladder cancer, breast cancer,cervical cancer, colorectal cancer, endometrial cancer, gastric cancer,head and neck cancer, kidney cancer, liver cancer, lung cancer, ovariancancer, prostate cancer, esophageal cancer, gall bladder cancer,pancreatic cancer, thyroid cancer, skin cancer. leukemia, multiplemyeloma, chronic lymphocytic lymphoma, adult T cell leukemia, B-celllymphoma, acute myelogenous leukemia, Hodgkin's or non-Hodgkin'slymphoma, Waldenstrom's Macroglubulinemia, hairy cell lymphoma,Burkett's lymphoma, glioblastoma, melanoma, and rhabdosarcoma.
 39. Amethod of treating a myeloproliferative disorder in a patient comprisingadministering to said patient a therapeutically effective amount of acompound of claim 1, or a pharmaceutically acceptable salt thereof. 40.The method of claim 39 wherein said myeloproliferative disorder isselected from polycythemia vera (PV), essential thrombocythemia (ET),and primary myelofibrosis (PMF).
 41. A method of treating a skeletal orchondrocyte disorder in a patient comprising administering to saidpatient a therapeutically effective amount of a compound of claim 1, ora pharmaceutically acceptable salt thereof.
 42. The method of claim 41wherein said skeletal or chondrocyte disorder is selected fromachrondroplasia, hypochondroplasia, dwarfism, thanatophoric dysplasia(TD), Apert syndrome, Crouzon syndrome, Jackson-Weiss syndrome,Beare-Stevenson cutis gyrate syndrome, Pfeiffer syndrome, andcraniosynostosis syndrome.